Squaramide-catalyzed asymmetric intramolecular oxa-michael reaction of α,β-unsaturated carbonyls containing benzyl alcohol: Construction of chiral 1-substituted phthalans

Article abstract of DOI:10.1021/acs.joc.1c00715

Organocatalytic enantioselective intramolecular oxa-Michael reactions of benzyl alcohol bearing α,β-unsaturated carbonyls as Michael acceptors are presented herein. Using cinchona squaramide-based organocatalyst, enones as well as α,βunsaturated esters containing benzyl alcohol provided their corresponding 1,3-dihydroisobenzofuranyl-1-methylene ketones and 1,3-dihydroisobenzofuranyl-1-methylene esters in excellent yields with high enantioselectivities. In addition, enantioenriched 1,3-dihydroisobenzofuranyl-1-methylene ketone could be obtained from the Wittig/oxa-Michael reaction cascade of 1,3-dihydro-2-benzofuran-1-ol.

Full text of DOI:10.1021/acs.joc.1c00715

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Squaramide-Catalyzed Asymmetric Intramolecular Oxa-Michael
Reaction of α,β-Unsaturated Carbonyls Containing Benzyl Alcohol:
Construction of Chiral 1‑Substituted Phthalans
Eun Chae Son, Seung Yeon Kim, and Sung-Gon Kim*
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ABSTRACT: Organocatalytic enantioselective intramolecular oxa-Michael reactions of benzyl alcohol bearing α,β-unsaturated
carbonyls as Michael acceptors are presented herein. Using cinchona squaramide-based organocatalyst, enones as well as α,β-
unsaturated esters containing benzyl alcohol provided their corresponding 1,3-dihydroisobenzofuranyl-1-methylene ketones and 1,3-
dihydroisobenzofuranyl-1-methylene esters in excellent yields with high enantioselectivities. In addition, enantioenriched 1,3-
dihydroisobenzofuranyl-1-methylene ketone could be obtained from the Wittig/oxa-Michael reaction cascade of 1,3-dihydro-2-
benzofuran-1-ol.
synthesis of chiral oxygen-containing heterocycles through the
combination of cascade reactions and utilization of organo-
catalysts.6 The catalytic asymmetric intramolecular oxa-Michael
reaction (AIOM) strategy has been used to directly and
effectively access chiral tetrahydrofuran (THF), tetrahydropyr-
an (THP), 2,3-dihydrobenzofuran, and chromane rings.1,7 In
2012, Matsubara and co-worker succeeded in the enantiose-
lective intramolecular oxa-Micheal reaction of ε-hydroxy-α,β-
unsaturated ketone substrates catalyzed by a cinchona thiourea-
based bifunctional organocatalyst for the construction of chiral
THF and THP.7a Subsequently, Zhao and co-workers reported
the chiral primary−secondary diamine-catalyzed AIOM of α,β-
unsaturated ketone substrates bearing a pendant hydroxyl
group yielding enantioenriched THF and THP.7b In 2018,
Song and co-workers developed a highly efficient chiral
cooperative cation-binding catalyst system for AIOM.7c
INTRODUCTION
■
Oxygen-containing heterocycles are privileged motifs and have
attracted immense attention in recent times due to their
widespread presence in natural products and biologically active
compounds, as well as their increasing importance in the fields
of pharmaceuticals and fine chemicals. Therefore, the develop-
ment of new synthetic methodologies for these oxacyclic
frameworks, especially in their chiral forms, is of great interest
in organic synthesis.1 In particular, chiral 1,3-dihydroisobenzo-
furan, commonly referred to as phthalan, is abundant in
bioactive natural products, which display pharmacological
properties such as antibacterial, anti-inflammatory, antidepres-
sive, antioxidant, and anti-influenza (Figure 1).2 Several
synthetic methods have been developed for phthalans based
on cyclization strategies.3 However, most reactions are limited
to the synthesis of nonchiral phthalans. Catalytic asymmetric
synthesis of chiral phthalans is still a particularly challenging
task, and only a few catalytic methods are known.4
Received: March 26, 2021
Published: April 27, 2021
The oxa-Michael reaction, conjugate addition of oxygen-
centered nucleophiles to α,β-unsaturated compounds, is one of
the simplest and most direct strategies to develop carbon−
oxygen bonds.5 In the last decade, the asymmetric catalytic oxa-
Micheal reaction has been used as a powerful tool in the
https://doi.org/10.1021/acs.joc.1c00715
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Figure 1. Biologically active chiral compounds containing the 1,3-dihydroisobenzofuran scaffold.
Scheme 1. Approaches for the Synthesis of Enantioenriched 1-Substituted 1,3-Dihydroisobenzofurans
The enantioselective synthesis of chromane using AIOM was
achieved well ahead of that of THF and THP.8 In 2004,
Merschaert and co-workers established the cinchona alkaloid-
catalyzed AIOM of α,β-unsaturated esters bearing phenol to
afford 2-substituted chiral chromanes.8a In 2013, similar results
for the synthesis of enantioenriched dihydrobenzofuranyl
acetates were presented by Hintermann and co-workers.8b
Soon after, the AIOM of α,β-unsaturated ketones bearing
phenol, catalyzed by a bifunctional cinchona thiourea catalyst,
generating optically active chromanes was reported by
Matsubara and co-workers.8d Takemoto and co-workers
developed methods for the AIOM of α,β-unsaturated amides
bearing phenol and α,β-unsaturated carboxylic acids bearing
phenol catalyzed by chiral aminobenzothiadiazine and chiral
aminothiourea, respectively.8c,e
considerably less attention and not been described thus far.
There are still challenging issues associated with this AIOM
that would need to be addressed, including its rapid cyclization
and reversibility. In addition, the difficulty in the synthesis of
α,β-unsaturated ketones bearing benzyl alcohol prevented this
type of AIOM.9d,e To overcome such challenges and synthesize
chiral 1,3-dihydroisobenzofuran, Ghorai and co-workers
established the AIOM of α,β-unsaturated ketones bearing
benzyloxyboronate, generated in situ from o-formyl chalcones
catalyzed by a squaramide organocatalyst affording enantioen-
riched 1,3-dihydroisobenzofuranyl-1-methylene aromatic ke-
tones (Scheme 1a).4c The synthetic approach for enantioen-
riched 1,3-dihydroisobenzofuranyl-1-methylene esters was also
reported by Blakey and co-workers, in which enantioselective
C−H insertion of ethyl diazoacetates into phthalan was
achieved using an Ir(III)-phebim catalyst (Scheme 1b).4d
Nevertheless, we still questioned the feasibility of the direct
AIOM of α,β-unsaturated carbonyl substrates bearing benzyl
Despite the aforementioned achievements, the AIOM of α,β-
unsaturated carbonyl substrates bearing a benzyl alcohol
group,9 affording chiral 1,3-dihydroisobenzofuran, has received
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alcohol. If α,β-unsaturated carbonyl substrates bearing benzyl
alcohol are synthesized more easily and subsequent AIOM is
possible, chiral 1-substituted phthalan could be easily accessed
(Scheme 1c). For this reason, we have revisited this direct
AIOM through careful investigation. Herein, we report the
direct AIOM of β-unsaturated carbonyl substrates (ketones and
esters) bearing benzyl alcohol using a cinchona squaramide-
based organocatalyst.
attention to determine the optimal catalyst for high
enantioselectivity.
With the optimized conditions in hand, we next examined
the generality of the quinidine-derived squaramide-catalyzed
AIOM (Scheme 2). β-(2-Hydroxymethyl)phenyl α,β-unsatu-
rated aromatic ketones 1a−g bearing different aromatics such
as para- or meta-substituted phenyl groups smoothly
participated in the intramolecular oxa-Michael reaction to
furnish enantioenriched phthalan products 2a−g in good to
excellent yields with high enantioselectivities. Moreover,
heteroaryls such as 2-furyl (2h) and 2-thiophenyl (2i) on the
enone successfully underwent AIOM in excellent yields with 86
and 89% ee, respectively. Additionally, substitution on the
central aryl moiety was tested under the optimized reaction
conditions. Regardless of the electron nature and position of
the R group in the aromatic ring, substituents such as Me (2j
and 2k), MeO (2l), Br (2m and 2n), Cl (2o), F (2p), F3C
(2q), and NO2 (2r) were well tolerated and provided
outstanding enantioselectivities (83−94% ee). The absolute
configurations of phthalans 2 were confirmed by comparison
with Ghorai’s work.4c
RESULTS AND DISCUSSION
■
First, a variety of β-(2-hydroxymethyl)phenyl α,β-unsaturated
carbonyl compounds 1 and 3 were successfully synthesized in
three steps from o-methylbenzoic acids via modified previously
reported procedures.10 Our asymmetric catalytic studies were
initiated with the intramolecular oxa-Michael reaction of (E)-3-
(2-(hydroxymethyl)phenyl)-1-phenylprop-2-en-1-one 1a using
5 mol % of the Takemoto bifunctional thiourea catalyst Ia11
(Table 1). When the reaction was conducted for 30 h in
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
catalyst
solvent
time (h)
yield (%)
ee
1
2
3
4
5
6
7
8
I
IIa
lib
Ilia
Illb
IVa
IVb
IVc
IVd
Va
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
o-xylene
m-xylene
p-xylene
CF3C6H5
CH2Cl2
CH3CN
THF
30
8
6
6
6
2
2
24
2
2
2
28
2
3
6
3
3
2
97
96
97
96
95
92
99
90
96
93
96
90
95
97
95
95
90
93
91
91
66
87
82
56
66
75
73
70
86
88
85
91
89
90
83
90
89
89
90
94
91
88
80
71
92
89
9
10
11
12
13
14
15
16
17
18
19
20
21
Vb
Vc
Vd
A variety of chiral bifunctional alkaloid organocatalysts were
screened in this AIOM (Table 1). Cinchona-derived thiourea-
based catalysts12 provided excellent yields with 66−75% ee
(Table 1, entries 2−5). On the other hand, cinchona-derived
squaramide-based catalysts13 also showed excellent yields with
high enantioselectivites (83−90% ee, Table 1, entries 6−13).
Squaramide catalysts featuring a methoxy group on the
quinolone moiety exhibited higher enantioselectivities (Table
1, entries 6 and 8 vs entries 7 and 9, entries 10 and 12 vs entries
11 and 13). Among the bifunctional squaramides tested (see
Table S1 in the Supporting Information), 3,5-bis-
(trifluoromethyl)benzylamine-containing quinidine-derived
squaramide IVd was found to be the optimal catalyst in
terms of reactivity and enantioselectivity (96% yield, 91% ee,
Table 1, entry 9). To further optimize the reaction conditions,
screening of various organic solvents such as toluene, o-xylene,
m-xylene, p-xylene, CF3C6H5, CH2Cl2, CH3CN, and THF was
performed using IVd (Table 1, entries 14−20). In CF3C6H5, an
increase in enantioselectivity to 94% ee was observed while
maintaining the yield (Table 1, entry 17). Interestingly, the
AIOM using IVd exhibited enantio-induction resulting in 71%
ee even in protic solvents such as MeOH (Table 1, entry 21).
Lowering the reaction temperature and catalyst loading did not
increase reactivity or enantioselectivity (Table 1, entries 22 and
23).
IVd
IVd
IVd
IVd
IVd
IVd
IVd
IVd
IVd
IVd
24
120
120
48
3
MeOH
CF3C6H5
CF3C6H5
d
22
23
e
a
The reactions were carried out in solvent (0.5 M) with 1a (0.1
b
mmol) and catalyst (5 mol %). After chromatographic purification.
c
Determined by chiral-phase high-performance liquid chromatog-
d
e
raphy (HPLC) analysis. Reaction carried out at 0 °C. 2 mol %
catalyst used.
toluene at room temperature, phthalan 2a was obtained in 97%
yield with moderate enantioselectivity (56% enantiomeric
excess (ee), Table 1, entry 1). Having identified the chiral
discrimination by the hydrogen-bonding interactions as the
activation mode for this AIOM reaction, we turned our
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a b c
, ,
Scheme 2. Substrate Scope of β-(2-(Hydroxymethyl)phenyl) α,β-Unsaturated Aromatic Ketones
a
b
The reactions were carried out in CF3C6H5 (0.5 M) with 1 (0.2 mmol) and IVd (5 mol %). Yield after chromatographic purification.
c
Determined by chiral-phase HPLC analysis.
After accomplishing the AIOM of β-(2-hydroxymethyl)-
phenyl α,β-unsaturated aromatic ketones 1, we attempted to
broaden the scope of enones to deliver 1-substituted 1,3-
dihydroisobenzofurans. The β-(2-hydroxymethyl)phenyl α,β-
unsaturated esters 3 were applied in this AIOM (Scheme 3).
α,β-Unsaturated esters 3 were less reactive than α,β-
unsaturated aromatic ketones 1; therefore, the reaction
proceeded at 50 °C and provided slightly reduced but still
high enantioselectivities (80−87% ee). Irrespective of the ester
type, the reactions proceeded smoothly to give the correspond-
ing phthalans 4a−c in good yields and with high
enantioselectivities. Among the esters, benzyl ester 3c
efficiently furnished the corresponding product 4c with the
best results (81% yield, 85% ee). A series of β-(2-
hydroxymethyl)phenyl α,β-unsaturated benzyl esters 3d−m
bearing various R groups on the central aryl moiety, regardless
of the electron nature and position of the R group, were
suitable substrates for this reaction and afforded phthalans 4d−
m in good to excellent yields with high enantioselectivities.
Ethyl ester substrates 3o−q bearing Br or Cl groups on the aryl
ring were less reactive than the benzyl ester substrates, and the
reactions were conducted at 80 °C, delivering products 4o−q
in high yields with 79−80% ee. The absolute configurations of
1,3-dihydroisobenzofuranyl-1-methylene esters 4 were con-
firmed by comparison with Blakey’s work.4d
This strategy was also applied to substrates containing
aliphatic ketones. β-(2-Hydroxymethyl)phenyl α,β-unsaturated
methyl ketone 5 efficiently furnished phthalan 6 in 95% yield
and 78% ee (Scheme 4A). More importantly, we further
examined the possibility of a Wittig/AIOM cascade reaction of
1,3-dihydro-2-benzofuran-1-ol. Interestingly, though the reac-
tion was not optimized, the one-pot reaction of 1,3-dihydro-2-
benzofuran-1-ol 7 with triphenyl phosphonium ylide 8 using
the quinidine-derived squaramide IVd catalyst in CF3C6H5 at
room temperature provided the corresponding phthalan 2a in
moderate yield (58%) and with a good enantioselectivity of
84% ee (Scheme 4B).14
Next, to demonstrate the utility of this AIOM, we performed
a one-mmol-scale reaction and synthetic transformation
(Scheme 5). The one-mmol-scale reaction of β-(2-
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c c c
, ,
Scheme 3. Substrate Scope of β-(2-(Hydroxymethyl)phenyl) α,β-Unsaturated Esters
d
a
b
Stirred at 80 °C. The reactions were carried out in CF3C6H5 (0.5 M) with 1a (0.2 mmol) and IVd (5 mol %). Yield after chromatographic
c
purification. Determined by chiral-phase HPLC analysis.
Scheme 4. Further Extension of Substrate Scope and Reaction Conditions
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Scheme 5. Reaction Utility
hydroxymethyl)phenyl α,β-unsaturated phenyl ketone 1a
successfully produced to give product 2a, retaining a high
yield of 95% with a similar enantioselectivity of 90% ee
(Scheme 5A). In addition, Cl group-containing phthalan 4j was
reduced by the treatment of LiAlH4 at room temperature,
thereby producing the corresponding phthalanyl alcohol 9 in
92% yield with 90% ee, which could be further transformed to
compound 10, which acts as a 5-HT1D antagonist. The increase
in ee value is thought to be caused by crystallization during
purification (Scheme 5B).
On the basis of our experimental results and previous
literature,13 a plausible transition state for this AIOM was
proposed to reveal the influence of the chiral bifunctional
squaramide catalyst on the enantioselectivity in Scheme 6. β-
with excellent yields, high enantioselectivities, and with a broad
substrate scope. In addition, enantioenriched 1,3-dihydroiso-
benzofuranyl-1-methylene ketone was obtained from the
Wittig/oxa-Michael reaction cascade of 1,3-dihydro-2-benzo-
furan-1-ol. The AIOM can be scaled up, and the synthetic
utility of the obtained 1,3-dihydroisobenzofuran was demon-
strated by further transformation.
EXPERIMENTAL SECTION
■
General Information. Organic solvents were distilled prior to use.
Organic solutions were concentrated under reduced pressure using a
rotary evaporator. Chromatographic purification of products was
accomplished using forced-flow chromatography on ICN 60 32−64
mesh silica gel 63. Thin-layer chromatography (TLC) was performed
on EM Reagents 0.25 mm silica gel 60-F plates. Developed
chromatograms were visualized by fluorescence quenching and with
Scheme 6. Plausible Transition State
1
anisaldehyde stain. H and 13C NMR spectra were recorded (400
MHz for 1H and 100 MHz for 13C) and were internally referenced to
residual protic solvent signals. Data for 1H NMR are reported as
follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t
= triplet, q = quartet, m = multiplet), coupling constant (Hz), and
integration. Data for 13C NMR are reported in terms of chemical shift.
IR spectra were recorded on an Fourier transform infrared (FTIR)
spectrometer and are reported in wave numbers. Optical rotations
were taken on a digital polarimeter. High-resolution mass spectros-
copy (HRMS) was performed by an electron impact ionization (EI-
magnetic sector) mass spectrometer. Enantiomeric excesses were
determined using an HPLC instrument with Chiralpak columns as
noted.
Typical Procedure for β-(2-(Hydroxymethyl)phenyl) α,β-
Unsaturated Carbonyl Compounds.10 To a solution of
alkylbenzoic acid (3.0 mmol) and Na2S2O8 (2.1 g, 9.0 mmol) in
CH3CN (15 mL) was added tetrabutylammonium bromide (TBAB,
1.9 g, 6.0 mmol) at room temperature. The reaction mixture was
stirred at 80 °C in an oil bath until alkylbenzoic acid was almost
consumed, as determined by TLC. Then, the resulting mixture was
diluted with water and extracted with EtOAc. The organic layer was
washed with aqueous (aq) NaHCO3 and brine gradually and dried
over MgSO4. The solvent was removed under reduced pressure. The
crude residue was purified by flash column chromatography with
EtOAc/hexane as an eluent to afford the desired phthalide. Next, to a
stirred solution of phthalide (1.0 mmol) in CH2Cl2 (5 mL) was added
diisobutylaluminum hydride (DIBAL-H) (1.1 mmol, 1.2 M in
toluene) at −78 °C. After stirring for 10 min, the reaction was
quenched with sat. Na2SO4 (0.5 mL) and allowed to warm to room
temperature. After adding additional dry Na2SO4, the resulting
mixture was stirred for 1 h and filtered through a plug of celite. The
organic residue was concentrated in vacuo to give desired 1,3-dihydro-
2-benzofuran-1-ol (including 2-(hydroxymethyl)benzaldehyde tauto-
mer), which was used in the Wittig reaction without further
(2-Hydroxymethyl)phenyl α,β-unsaturated phenyl ketone 1a is
assumed to interact with the squaramide of catalyst IVd by
double hydrogen bonding, which fixes and activates the
substrate in a bidentate interaction. Meanwhile, the hydrox-
ymethyl moiety is deprotonated by the basic nitrogen atom of
the tertiary amine moiety in the catalyst; the deprotonated
oxygen atom is assumed to interact with the protonated amine
by hydrogen bonding. Thereafter, the sterically crowded
organocatalyst dominates so that the oxygen atom of
hydroxymethyl moiety attacks at the Re face of the enone,
leading to the intramolecular attack affording the desired S-
configurational product 2a.
CONCLUSIONS
■
In summary, an AIOM of benzyl alcohol bearing α,β-
unsaturated carbonyls as Michael acceptors, using a chiral
cinchona squaramide-based organocatalyst, has been devel-
oped. 1,3-Dihydroisobenzofuranyl-1-methylene ketones and
1,3-dihydroisobenzofuranyl-1-methylene esters are obtained
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purification. To a solution of 1,3-dihydro-2-benzofuran-1-ol (1.0
mmol) in CH2Cl2 (5 mL) was added triphenyl phosphonium ylide
(1.5 mmol) at 0 °C. The reaction mixture was stirred overnight at the
same temperature, allowed to warm to room temperature, and the
solvent was evaporated under reduced pressure. The crude residue was
purified by flash column chromatography with EtOAc/hexane as an
eluent to afford the desired α,β-unsaturated carbonyl containing
benzyl alcohol 1 or 3.
(E)-3-(2-(Hydroxymethyl)phenyl)-1-phenylprop-2-en-1-one
(1a).9e,f 188 mg, yield 79%, 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J
= 15.6 Hz, 1H), 8.12−7.98 (m, 2H), 7.83−7.72 (m, 1H), 7.64−7.57
(m, 1H), 7.57−7.31 (m, 6H), 4.89 (d, J = 5.3 Hz, 2H), 1.84 (t, J = 5.4
Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.6, 141.6, 140.1,
138.2, 133.8, 133.0, 130.5, 129.0, 128.8, 128.7, 128.5, 127.2, 124.4,
63.2.
(E)-3-(2-(Hydroxymethyl)phenyl)-1-(p-tolyl)prop-2-en-1-one
(1b). 200 mg, yield 79%, 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J =
15.6 Hz, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.81−7.69 (m, 1H), 7.54−7.33
(m, 4H), 7.30 (d, J = 7.9 Hz, 2H), 4.88 (d, J = 5.4 Hz, 2H), 2.44 (s,
3H), 2.03 (t, J = 5.5 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
190.1, 143.9, 141.2, 140.1, 135.6, 133.9, 130.4, 129.5, 129.0, 128.9,
128.4, 127.1, 124.4, 63.1, 21.8; HRMS (EI) m/z calcd for [M]+
C17H16O2: 252.1150, found: 252.1174.
(E)-3-(2-(Hydroxymethyl)phenyl)-1-(4-methoxyphenyl)prop-2-
en-1-one (1c).9e,f 109 mg, yield, 41%, 1H NMR (400 MHz, CDCl3) δ
8.12 (d, J = 15.5 Hz, 1H), 8.08−7.98 (m, 2H), 7.73 (dd, J = 7.5, 1.4
Hz, 1H), 7.58−7.31 (m, 4H), 7.04−6.92 (m, 2H), 4.89 (brs, 2H),
3.89 (s, 3H), 2.00 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
188.8, 163.6, 140.8, 140.1, 134.0 (two peaks overlapped), 131.1, 130.3,
129.0, 128.4, 127.1, 124.3, 114.0, 63.1, 55.6.
J = 15.5 Hz, 1H), 7.88 (dd, J = 3.8, 1.0 Hz, 1H), 7.80−7.65 (m, 2H),
7.52−7.34 (m, 4H), 7.19 (dd, J = 4.9, 3.8 Hz, 1H), 4.89 (d, J = 3.4 Hz,
2H), 1.98 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 182.2,
145.5, 140.9, 140.2, 134.2, 133.6, 132.2, 130.6, 129.0, 128.4, 128.4,
127.2, 124.0, 63.1.
(E)-3-(2-(Hydroxymethyl)-4-methylphenyl)-1-phenylprop-2-en-
1
1-one (1j). 121 mg, yield, 48%, H NMR (400 MHz, CDCl3) δ 8.13
(d, J = 15.6 Hz, 1H), 8.05−8.01 (m, 2H), 7.66 (d, J = 7.9 Hz, 1H),
7.60−7.46 (m, 4H), 7.30 (s, 1H), 7.19 (d, J = 7.9 Hz, 1H), 4.86 (d, J =
5.0 Hz, 2H), 2.40 (s, 3H), 1.87 (t, J = 5.3 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 190.68, 141.57, 141.09, 140.13, 138.34, 132.94,
130.88, 129.84, 129.17, 128.76, 128.70, 127.18, 123.27, 63.15, 21.61;
HRMS (EI) m/z calcd for [M]+ C17H16O2: 252.1150, found:
252.1170.
(E)-3-(2-(Hydroxymethyl)-5-methylphenyl)-1-phenylprop-2-en-
1-one (1k).9e 179 mg, yield, 71%, 1H NMR (400 MHz, CDCl3) δ 8.14
(d, J = 15.6 Hz, 1H), 8.03 (dd, J = 5.2, 3.3 Hz, 2H), 7.61−7.47 (m,
5H), 7.35 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 4.84 (d, J = 5.1
Hz, 2H), 2.40 (s, 3H), 1.91 (t, J = 5.0 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 190.6, 141.8, 138.2, 138.2, 137.4, 133.7, 133.0, 131.3,
129.3, 128.8, 128.7, 127.7, 124.0, 63.0, 21.3.
(E)-3-(2-(Hydroxymethyl)-3-methoxyphenyl)-1-phenylprop-2-en-
1-one (1l). 67 mg, yield, 25%, 1H NMR (400 MHz, CDCl3) δ 8.19 (d,
J = 15.6 Hz, 1H), 8.07−7.97 (m, 2H), 7.62−7.56 (m, 1H), 7.54−7.43
(m, 3H), 7.37−7.30 (m, 2H), 6.97 (dd, J = 7.5, 1.6 Hz, 1H), 4.89 (brs,
2H), 3.91 (s, 3H), 2.21 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3)
δ 190.6, 158.5, 142.1, 138.2, 135.9, 133.0, 129.3, 128.8, 128.8, 128.5,
125.8, 119.8, 112.1, 56.7, 55.9; HRMS (EI) m/z calcd for [M]+
C17H16O3: 268.1099, found: 268.1087.
(E)-3-(4-Bromo-2-(hydroxymethyl)phenyl)-1-phenylprop-2-en-1-
one (1m). 149 mg, yield, 47%, 1H NMR (400 MHz, CDCl3) δ 78.07−
7.96 (m, 3H), 7.69 (d, J = 2.0 Hz, 1H), 7.64−7.57 (m, 2H), 7.56−7.45
(m, 4H), 4.87 (d, J = 5.4 Hz, 2H), 1.89 (t, J = 5.5 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 190.2, 142.0, 140.2, 138.0, 133.2, 132.4,
131.6, 131.4, 128.9, 128.7, 128.5, 124.8, 124.6, 62.4; HRMS (EI) m/z
calcd for [M]+ C16H13BrO2: 316.0099, found: 316.0115.
(E)-1-(4-Fluorophenyl)-3-(2-(hydroxymethyl)phenyl)prop-2-en-1-
one (1d). 166 mg, yield 65%, 1H NMR (400 MHz, CDCl3) δ 8.15 (d,
J = 15.5 Hz, 1H), 8.11−7.99 (m, 2H), 7.80−7.67 (m, 1H), 7.53−7.34
(m, 4H), 7.23−7.11 (m, 2H), 4.88 (d, J = 4.7 Hz, 2H), 1.91 (brs, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 188.9, 165.8 (d, J1 = 254.7 Hz),
141.9, 140.1, 134.5 (d, J4 = 2.9 Hz), 133.8, 131.3 (d, J3 = 9.3 Hz),
130.6, 129.1, 128.5, 127.2, 123.9, 115.9 (d, J2 = 21.8 Hz), 63.2; HRMS
(EI) m/z calcd for [M]+ C16H13FO2: 256.0900, found: 256.0927.
(E)-1-(4-Bromophenyl)-3-(2-(hydroxymethyl)phenyl)prop-2-en-
1-one (1e). 82 mg, yield, 26%, 1H NMR (400 MHz, CDCl3) δ 8.16 (d,
J = 15.6 Hz, 1H), 7.94−7.87 (m, 2H), 7.79−7.71 (m, 1H), 7.70−7.60
(m, 2H), 7.52−7.35 (m, 4H), 4.88 (d, J = 5.5 Hz, 2H), 1.76 (t, J = 5.5
Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 189.5, 142.2, 140.2,
136.9, 133.7, 132.1, 130.7, 130.3, 129.1, 128.5, 128.9, 127.2, 123.8,
63.3; HRMS (EI) m/z calcd for [M]+ C16H13BrO2: 316.0099, found:
316.0099.
(E)-3-(5-Bromo-2-(hydroxymethyl)phenyl)-1-phenylprop-2-en-1-
one (1n). 222 mg, yield, 70%, 1H NMR (400 MHz, CDCl3) δ 8.10−
7.99 (m, 3H), 7.85 (d, J = 2.0 Hz, 1H), 7.61 (ddd, J = 6.6, 3.9, 1.3 Hz,
1H), 7.55−7.47 (m, 4H), 7.38 (d, J = 8.2 Hz, 1H), 4.84 (d, J = 5.1 Hz,
2H), 1.91 (t, J = 5.3 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
190.0, 139.9, 139.0, 137.9, 135.7, 133.3, 133.2, 130.5, 129.8, 128.9,
128.8, 125.2, 122.3, 62.5; HRMS (EI) m/z calcd for [M]+
C16H13BrO2: 316.0099, found: 316.0104.
(E)-3-(5-Chloro-2-(hydroxymethyl)phenyl)-1-phenylprop-2-en-1-
1
one (1o). 131 mg, yield, 48%, H NMR (400 MHz, CDCl3) δ 8.10−
(E)-1-(4-Chlorophenyl)-3-(2-(hydroxymethyl)phenyl)prop-2-en-
1-one (1f). 95 mg, yield, 35%, 1H NMR (400 MHz, CDCl3) δ 8.16 (d,
J = 15.6 Hz, 1H), 8.04−7.92 (m, 2H), 7.79−7.69 (m, 1H), 7.54−7.34
(m, 6H), 4.88 (d, J = 5.4 Hz, 2H), 1.89 (t, J = 5.5 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 189.3, 142.2, 140.2, 139.5, 136.5, 133.7,
130.7, 130.1, 129.1, 129.1, 128.5, 127.2, 123.8, 63.2; HRMS (EI) m/z
calcd for [M]+ C16H13ClO2: 272.0604, found: 272.0601.
8.01 (m, 3H), 7.70 (d, J = 2.1 Hz, 1H), 7.64−7.58 (m, 1H), 7.55−7.42
(m, 4H), 7.38 (dd, J = 8.2, 2.1 Hz, 1H), 4.85 (brs, 2H), 1.94 (brs,
1H); 13C{1H} MR (100 MHz, CDCl3) δ 190.1, 140.0, 138.5, 137.9,
135.4, 134.2, 133.3, 130.3, 130.2, 128.9, 128.8, 126.9, 125.1, 62.5;
HRMS (EI) m/z calcd for [M]+ C16H13ClO2: 272.0604, found:
272.0619.
(E)-3-(5-Fluoro-2-(hydroxymethyl)phenyl)-1-phenylprop-2-en-1-
(E)-1-(3-Chlorophenyl)-3-(2-(hydroxymethyl)phenyl)prop-2-en-
one (1p).9f 164 mg, yield, 64%, H NMR (400 MHz, CDCl3) δ 8.09
1
1
1-one (1g). 87 mg, yield, 32%, H NMR (400 MHz, CDCl3) δ 8.17
(dd, J = 15.6, 1.3 Hz, 1H), 8.03 (dd, J = 5.2, 3.3 Hz, 2H), 7.65−7.58
(m, 1H), 7.56−7.40 (m, 5H), 7.11 (td, J = 8.3, 2.6 Hz, 1H), 4.85 (d, J
= 5.1 Hz, 2H), 1.89 (t, J = 5.1 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 190.2, 162.6 (d, J1 = 246.9 Hz), 140.3 (d, J4 = 2.4 Hz),
137.9, 136.0 (d, J4 = 3.1 Hz), 135.9 (d, J3 = 7.7 Hz), 133.3, 131.1 (d, J3
= 8.3 Hz), 128.9, 128.7, 125.1, 117.2 (d, J2 = 21.3 Hz), 113.6 (d, J =
22.3 Hz), 62.54.
(E)-3-(2-(Hydroxymethyl)-5-(trifluoromethyl)phenyl)-1-phenyl-
prop-2-en-1-one (1q). 202 mg, yield, 66%, 1H NMR (400 MHz,
CDCl3) δ 8.09 (d, J = 15.7 Hz, 1H), 8.05 (d, J = 7.4 Hz, 2H), 7.94 (s,
1H), 7.67 (s, 2H), 7.62 (t, J = 7.3 Hz, 1H), 7.54 (dd, J = 15.1, 7.0 Hz,
3H), 4.95 (d, J = 4.9 Hz, 2H), 2.11 (t, J = 5.2 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 190.0, 143.6, 139.8, 137.8, 134.2, 133.4, 130.6
(q, J2 = 32.7, 32.7 Hz), 128.9, 128.84, 128.79, 126.8 (q, J3 = 3.7 Hz),
125.5, 124.0 (q, J1 = 272.3 Hz), 123.7 (q, J3 = 3.8 Hz), 62.5; HRMS
(EI) m/z calcd for [M]+ C17H13F3O2: 306.0868, found: 306.0867.
(d, J = 15.6 Hz, 1H), 8.00 (t, J = 1.8 Hz, 1H), 7.96−7.85 (m, 1H),
7.80−7.69 (m, 1H), 7.56 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H), 7.53−7.35
(m, 5H), 4.89 (d, J = 5.4 Hz, 2H), 1.84 (t, J = 5.4 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 189.3, 142.5, 140.2, 139.8, 135.1, 133.6,
132.9, 130.8, 130.1, 129.1, 128.8, 128.5, 127.2, 126.8, 123.7; HRMS
(EI) m/z calcd for [M]+ C16H13ClO2: 272.0604, found: 272.0619.
(E)-1-(Furan-2-yl)-3-(2-(hydroxymethyl)phenyl)prop-2-en-1-one
(1h). 125 mg, yield, 55%, 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J =
15.7 Hz, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.66 (d, J = 1.0 Hz, 1H), 7.53−
7.31 (m, 5H), 6.60 (dd, J = 3.6, 1.7 Hz, 1H), 4.90 (d, J = 4.7 Hz, 2H),
1.89 (t, J = 5.1 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.1,
153.8, 146.8, 140.7, 140.2, 133.6, 130.6, 129.0, 128.4, 127.2, 123.5,
117.9, 112.7, 63.1; HRMS (EI) m/z calcd for [M]+ C14H12O3:
228.0786, found: 228.0786.
(E)-3-(2-(Hydroxymethyl)phenyl)-1-(thiophen-2-yl)prop-2-en-1-
one (1i).9a 81 mg, yield, 33%, 1H NMR (400 MHz, CDCl3) δ 8.17 (d,
6832
https://doi.org/10.1021/acs.joc.1c00715
J. Org. Chem. 2021, 86, 6826−6839

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(E)-3-(2-Hydroxymethyl)-5-(nitrophenyl)-1-phenylprop-2-en-1-
one (1r). 116 mg, yield, 41%, 1H NMR (400 MHz, CDCl3) δ 8.56 (d,
J = 2.3 Hz, 1H), 8.27 (dd, J = 8.5, 2.3 Hz, 1H), 8.09−8.01 (m, 3H),
7.77 (d, J = 8.5 Hz, 1H), 7.67−7.61 (m, 2H), 7.58−7.52 (m, 2H), 5.01
(d, J = 5.3 Hz, 2H), 2.09 (t, J = 5.3 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 189.5, 147.8, 146. 7, 138.5, 133.6, 129.0, 128.9, 128.9,
128.8, 128.4, 126.3, 124.6, 121.6, 62.2; HRMS (EI) m/z calcd for
[M]+ C16H13NO4: 283.0845, found: 283.0854.
Benzyl (E)-3-(5-Bromo-2-(hydroxymethyl)phenyl)acrylate (3i).
260 mg, yield 75%, H NMR (400 MHz, CDCl3) δ 7.96 (d, J =
1
15.9 Hz, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.2, 1.9 Hz, 1H),
7.46−7.29 (m, 6H), 6.44 (d, J = 15.8 Hz, 1H), 5.26 (s, 2H), 4.78 (brs,
2H), 1.75 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.4,
140.5, 138.4, 136.0, 135.1, 133.1, 130.3, 129.8, 128.8, 128.5, 128.4,
122.3, 121.4, 66.7, 62.5; HRMS (EI) m/z calcd for [M]+ C17H15BrO3:
346.0205, found: 346.0225.
Methyl (E)-3-(2-(Hydroxymethyl)phenyl)acrylate (3a).9b,c 157 mg,
yield 82%, 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 15.9 Hz, 1H),
7.67−7.59 (m, 1H), 7.51−7.30 (m, 3H), 6.41 (d, J = 15.9 Hz, 1H),
4.84 (brs, 2H), 3.81 (s, 3H), 1.75 (brs, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 167.4, 141.7, 139.5, 133.3, 130.3, 128.9, 128.5, 127.0,
120.1, 63.2, 51.9.
Benzyl (E)-3-(4-Chloro-2-(hydroxymethyl)phenyl)acrylate (3j).
1
105 mg, yield 52%, H NMR (400 MHz, CDCl3) δ 77.95 (d, J =
15.9 Hz, 1H), 7.50 (dd, J = 12.4, 5.2 Hz, 2H), 7.44−7.27 (m, 6H),
6.42 (d, J = 15.8 Hz, 1H), 5.25 (s, 2H), 4.82 (brs, 2H), 1.81 (brs, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 166.6, 141.311, 140.631, 136.4,
136.0, 131.3, 128.8, 128.48 (two peaks overlapped), 128.46, 128.4,
128.3, 120.5, 66.7, 62.4; HRMS (EI) m/z calcd for [M]+ C17H15ClO3:
302.0710, found: 302.0721.
Ethyl (E)-3-(2-(Hydroxymethyl)phenyl)acrylate (3b).9d 128 mg,
yield 62%, 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 15.9 Hz, 1H),
7.61 (d, J = 7.5 Hz, 1H), 7.50−7.28 (m, 3H), 6.41 (d, J = 15.9 Hz,
1H), 4.85 (d, J = 5.4 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.72 (t, J = 5.5
Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 167.0, 141.4, 139.6, 133.3, 130.3, 128.8, 128.4, 127.0, 120.5, 63.1,
60.8, 14.5.
Benzyl (E)-3-(2-(Hydroxymethyl)phenyl)acrylate (3c). 169 mg,
yield 63%, 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 15.9 Hz, 1H),
7.65−7.58 (m, 1H), 7.48−7.32 (m, 8H), 6.46 (d, J = 15.9 Hz, 1H),
5.26 (s, 2H), 4.84 (d, J = 5.1 Hz, 2H), 1.79 (t, J = 5.4 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 166.8, 142.0, 139.6, 136.1, 133.2,
Benzyl (E)-3-(5-Chloro-2-(hydroxymethyl)phenyl)acrylate (3k).
1
200 mg, yield 66%, H NMR (400 MHz, CDCl3) δ 7.98 (d, J =
15.9 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.47−7.31 (m, 7H), 6.45 (d, J
= 15.8 Hz, 1H), 5.26 (s, 2H), 4.79 (s, 2H), 1.83 (s, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 166.4, 140.6, 137.9, 136.0, 134.8, 134.3,
130.2, 130.1, 128.8, 128.5, 128.4, 126.9, 121.3, 66.7, 62.4; HRMS (EI)
m/z calcd for [M]+ C17H15ClO3: 302.0710, found: 302.0704.
Benzyl (E)-3-(5-Fluoro-2-(hydroxymethyl)phenyl)acrylate (3l).
1
160 mg, yield 56%, H NMR (400 MHz, CDCl3) δ 8.02 (dd, J =
15.9, 1.4 Hz, 1H), 7.45−7.33 (m, 6H), 7.28 (dd, J = 9.7, 2.7 Hz, 1H),
7.07 (td, J = 8.3, 2.6 Hz, 1H), 6.44 (d, J = 15.8 Hz, 1H), 5.26 (s, 2H),
4.79 (d, J = 4.6 Hz, 2H), 1.76 (t, J = 5.0 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 166.4, 162.6 (d, J = 247.0 Hz), 140.9 (d, J = 3.1 Hz),
136.0, 135.5 (d, J = 3.1 Hz), 135.3 (d, J = 7.8 Hz), 130.9 (d, J = 8.3
Hz), 128.8, 128.48, 128.46, 121.2, 117.1 (d, J = 21.3 Hz), 113.6 (d, J =
22.4 Hz), 66.7, 62.5; HRMS (EI) m/z calcd for [M]+ C17H15FO3:
286.1005, found: 286.0976.
130.4, 128.9, 128.7, 128.5, 128.4, 128.4, 127.1, 120.1, 66.6, 63.1;
HRMS (EI) m/z calcd for [M]+ C17H16O3: 268.1099, found:
268.1083.
Benzyl (E)-3-(2-(Hydroxymethyl)-4-methylphenyl)acrylate (3d).
203 mg, yield 72%, 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 15.8
Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.47−7.29 (m, 6H), 7.14 (d, J = 8.0
Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 5.25 (s, 2H), 4.81 (brs, 2H), 2.37
(s, 3H), 1.68 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.1,
142.0, 141.0, 139.6, 136.34, 130.4, 129.8, 129.3, 128.8, 128.5, 128.5,
127.2, 119.1, 66.6, 63.2, 21.6; HRMS (EI) m/z calcd for [M]+
C18H18O3: 282.1256, found: 282.1268.
Benzyl (E)-3-(2-(Hydroxymethyl)-5-(trifluoromethyl)phenyl)-
1
acrylate (3m). 174 mg, yield 52%, H NMR (400 MHz, CDCl3) δ
8.01 (d, J = 16.0 Hz, 1H), 7.81 (s, 1H), 7.69−7.59 (m, 2H), 7.46−
7.33 (m, 5H), 6.51 (d, J = 15.9 Hz, 1H), 5.27 (s, 2H), 4.89 (brs, 2H),
1.85 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 143.1,
140.5, 135.8, 133.5, 130.59 (q, J2 = 32.7 Hz),128.8, 128.7, 128.53,
128.47, 126.7 (q, J3 = 3.6 Hz), 123.90 (q, J1 = 272.4 Hz), 123.74 (q, J3
= 3.8 Hz), 121.8, 66.8, 62.4; HRMS (EI) m/z calcd for [M]+
C18H15F3O3: 336.0973, found: 336.0965.
Benzyl (E)-3-(2-(Hydroxymethyl)-5-methylphenyl)acrylate (3e).
1
200 mg, yield 71%, H NMR (400 MHz, CDCl3) δ 8.08 (d, J =
15.9 Hz, 1H), 7.45−7.30 (m, 7H), 7.20 (d, J = 7.6 Hz, 1H), 6.46 (d, J
= 15.9 Hz, 1H), 5.26 (s, 2H), 4.79 (s, br, 2H), 2.36 (s, 3H), 1.64 (brs,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.8, 142.2, 138.3, 136.8,
136.2, 133.1, 131.2, 129.1, 128.7, 128.4, 128.4, 127.7, 119.9, 66.5, 63.0,
21.3; HRMS (EI) m/z calcd for [M]+ C18H18O3: 282.1256, found:
282.1248.
Benzyl (E)-3-(2-(Hydroxymethyl)-3-methoxyphenyl)acrylate (3f).
244 mg, yield 82%, 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 15.8
Hz, 1H), 7.47−7.26 (m, 6H), 7.18 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 8.1
Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 5.26 (s, 2H), 4.84 (brs, 2H), 3.89
(s, 3H), 2.19 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.6,
158.3, 142.4, 136.1, 135.1, 129.3, 128.7, 128.5, 128.4, 128.1, 121.3,
119.6, 111.9, 66. 6, 56.6, 55.9; HRMS (EI) m/z calcd for [M]+
C18H18O4: 298.1205, found: 298.1176.
Ethyl (E)-3-(2-(Hydroxymethyl)-3-methoxyphenyl)acrylate (3n).
1
158 mg, yield 67%, H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 15.8
Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 6.94 (d, J =
8.1 Hz, 1H), 6.37 (d, J = 15.8 Hz, 1H), 4.85 (brs, 2H), 4.27 (q, J = 7.1
Hz, 2H), 3.89 (s, 3H), 2.16 (brs, 1H), 1.34 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 166.8, 158.3, 141.8, 135.3, 129.3,
128.0, 121.8, 119.5, 111.8, 60.7, 56.6, 55.9, 14.5; HRMS (EI) m/z
calcd for [M]+ C13H16O4: 236.1049, found: 236.1054.
Ethyl (E)-3-(3-Bromo-2-(hydroxymethyl)phenyl)acrylate (3o).
1
231 mg, yield 81%, H NMR (400 MHz, CDCl3) δ 8.10 (d, J =
15.8 Hz, 1H), 7.61 (dd, J = 8.0, 1.1 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H),
7.20 (t, J = 7.9 Hz, 1H), 6.38 (d, J = 15.8 Hz, 1H), 4.94 (s, 2H), 4.28
(q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 166.7, 141.4, 140.1, 131.9, 131.4, 131.4, 128.4, 124.5,
121.1, 62.4, 60.9, 14.4; HRMS (EI) m/z calcd for [M]+ C12H13BrO3:
284.0048, found: 284.0074.
Benzyl (E)-3-(3-Bromo-2-(hydroxymethyl)phenyl)acrylate (3g).
1
291 mg, yield 84%, H NMR (400 MHz, CDCl3) δ 8.15 (d, J =
15.8 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.46−
7.33 (m, 5H), 7.19 (t, J = 7.9 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 5.26
(s, 2H), 4.94 (brs, 2H), 1.99 (brs, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 166.3, 142.2, 138.0, 137.0, 136.0, 134.4, 130.0, 128.8, 128.5,
128.5, 126.9, 126.2, 122.3, 66.7, 61.8; HRMS (EI) m/z calcd for [M]+
C17H15BrO3: 346.0205, found: 346.0214.
Ethyl (E)-3-(4-Bromo-2-(hydroxymethyl)phenyl)acrylate (3p).
1
165 mg, yield 58%, H NMR (400 MHz, CDCl3) δ 7.89 (d, J =
15.8 Hz, 1H), 7.64 (s, 1H), 7.45 (s, 2H), 6.38 (d, J = 15.8 Hz, 1H),
4.82 (brs, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.81 (brs, 1H), 1.34 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.5, 141.6, 137.9,
137.1, 134.3, 130.0, 126.9, 126.2, 122.8, 61.8, 60.9, 14.5; HRMS (EI)
m/z calcd for [M]+ C12H13BrO3: 284.0048, found: 284.0025.
Ethyl (E)-3-(4-Chloro-2-(hydroxymethyl)phenyl)acrylate (3q).
Benzyl (E)-3-(4-Bromo-2-(hydroxymethyl)phenyl)acrylate (3h).
1
187 mg, yield 54%, H NMR (400 MHz, CDCl3) δ 7.94 (d, J =
15.8 Hz, 1H), 7.64 (s, 1H), 7.54−7.29 (m, 7H), 6.43 (d, J = 15.8 Hz,
1H), 5.25 (s, 2H), 4.81 (brs, 2H), 1.79 (brs, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 166.5, 141.45, 140.7, 136.0, 131.8, 131.5, 131.4,
128.8 (two peaks overlapped), 128.5 (two peaks overlapped), 124.7,
120.6, 66.7, 62.4; HRMS (EI) m/z calcd for [M]+ C17H15BrO3:
346.0205, found: 346.0201.
1
142 mg, yield 59%, H NMR (400 MHz, CDCl3) δ 7.90 (d, J =
15.9 Hz, 1H), 7.51 (dd, J = 14.0, 5.2 Hz, 2H), 7.30 (dd, J = 8.3, 2.1
Hz, 1H), 6.37 (d, J = 15.8 Hz, 1H), 4.83 (s, 2H), 4.27 (q, J = 7.1 Hz,
2H), 1.82 (s, 1H), 1.34 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz,
6833
https://doi.org/10.1021/acs.joc.1c00715
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The Journal of Organic Chemistry
pubs.acs.org/joc
Article
CDCl3) δ 166.8, 141.2, 140.0, 136.2, 131.4, 128.5, 128.4, 128.3, 121.0,
62.5, 60.9, 14.4; HRMS (EI) m/z calcd for [M]+ C12H13ClO3:
240.0553, found: 240.0565.
12.2, 1.6 Hz, 2H), 3.51 (dd, J = 16.5, 7.4 Hz, 1H), 3.31 (dd, J = 16.5,
4.9 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 196.4, 166.00 (d, J1
= 255.0 Hz), 141.4, 139.3, 133.70 (d, J4 = 3.0 Hz), 131.12 (d, J3 = 9.4
Hz), 128.0, 127.6, 121.6, 121.2, 115.86 (d, J2 = 21.9 Hz), 80.3, 72.8,
45.7; IR (neat) 3074, 2916, 2852, 1681, 1594, 1505, 1479, 1462, 1410,
1352, 1319, 1300, 1224, 1207, 1155, 1100, 1035 cm−1; HRMS (EI)
m/z calcd for [M]+ C16H13FO2: 256.0900, found: 256.0886; Chiralpak
OJ-H column and OJ-H guard column, 5% i-PrOH/hexanes, 1.0 mL/
min flow, λ = 254 nm, major-isomer tr = 21.8 min and minor-isomer tr
= 28.4 min.
(S)-1-(4-Bromophenyl)-2-(1,3-dihydroisobenzofuran-1-yl)ethan-
1-one (2e).4c Synthesized by the general procedure I; flash
chromatography (EtOAc/hexane = 1:10, 62 mg, yield 98%), white
solid; m.p. 101−103 °C; [α]2D8 = −6.03 (c = 0.40, CHCl3); 91% ee; 1H
NMR (400 MHz, CDCl3) δ 7.89−7.80 (m, 2H), 7.65−7.55 (m, 2H),
7.32−7.21 (m, 4H), 5.87 (td, J = 5.1, 2.4 Hz, 1H), 5.20−5.03 (m,
2H), 3.49 (dd, J = 16.5, 7.4 Hz, 1H), 3.31 (dd, J = 16.5, 4.9 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 197.0, 141.3, 139.3, 136.0, 132.1,
(E)-4-(2-(Hydroxymethyl)phenyl)but-3-en-2-one (5).9a,f 1H NMR
(400 MHz, CDCl3) δ 7.93 (d, J = 16.2 Hz, 1H), 7.69−7.59 (m, 1H),
7.49−7.32 (m, 3H), 6.68 (d, J = 16.1 Hz, 1H), 4.85 (d, J = 4.3 Hz,
2H), 2.40 (s, 3H), 1.76 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3)
δ 198.7, 140.3, 139.7, 133.5, 130.5, 129.1, 128.7, 127.0, 63.4, 27.8.
General Procedure I for Asymmetric Intramolecular Oxa-
Michael Reaction of β-(2-(Hydroxymethyl)phenyl) α,β-Unsa-
turated Ketones. To a solution of β-(2-(hydroxymethyl)phenyl)
α,β-unsaturated ketone 1 (0.20 mmol, 1.0 equiv) in trifluorotoluene
(0.4 mL) was added catalyst IVd (0.010 mmol, 0.05 equiv) at room
temperature. The reaction mixture was stirred at the same temperature
until β-(2-(hydroxymethyl)phenyl) α,β-unsaturated ketone 1 was
completely consumed, as determined by TLC. Then, the resulting
mixture was diluted with EtOAc/hexane (1:1), filtered through a plug
of celite, and concentrated in vacuo. The crude residue was purified by
flash column chromatography with EtOAc/hexane as an eluent to
afford the desired product 2.
130.0, 128.6, 128.0, 127.6, 121.6, 121.2, 80.3, 72.8, 45.7; IR (neat)
2924, 2855, 1727, 1680, 1651, 1580, 1566, 1514, 1503, 1481, 1461,
1392, 1305, 1253, 1194, 1141, 1102, 1032 cm−1; HRMS (EI) m/z
calcd for [M]+ C16H13BrO2: 316.0099, found: 316.0114; Chiralpak
OJ-H column and OJ-H guard column, 5% i-PrOH/hexanes, 1.0 mL/
min flow, λ = 254 nm, major-isomer tr = 26.2 min and minor-isomer tr
= 31.9 min.
(S)-2-(1,3-Dihydroisobenzofuran-1-yl)-1-phenylethan-1-one
(2a).4c Synthesized by the general procedure I; flash chromatography
(EtOAc/hexane = 1:10, 43 mg, yield 90%), white solid; m.p. 83−85
1
°C; [α]2D8 = −16.2 (c = 0.40, CHCl3); 94% ee; H NMR (400 MHz,
CDCl3) δ 8.06−7.91 (m, 2H), 7.65−7.54 (m, 1H), 7.50−7.40 (m,
2H), 7.34−7.22 (m, 4H), 5.91 (ddd, J = 7.1, 4.8, 2.2 Hz, 1H), 5.22−
4.99 (m, 2H), 3.55 (dd, J = 16.7, 7.3 Hz, 1H), 3.35 (dd, J = 16.7, 5.1
Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.0, 141.6, 139.4,
137.2, 133.4, 128.7, 128.4, 127.9, 127.6, 121.6, 121.2, 80.3, 72.8, 45.8
cm−1; IR (neat) 2910.2860, 1678, 1595, 1576, 1476, 1448, 1402,
1357, 1299, 1286, 1207, 1177, 1103, 1018 cm−1; HRMS (EI) m/z
calcd for [M]+ C16H14O2: 238.0994, found: 238.1006; Chiralpak OJ-H
column and OJ-H guard column, 5% i-PrOH/hexanes, 1.0 mL/min
flow, λ = 254 nm, major-isomer tr = 24.7 min and minor-isomer tr =
34.6 min.
(S)-1-(4-Chlorophenyl)-2-(1,3-dihydroisobenzofuran-1-yl)ethan-
1-one (2f).4c Synthesized by the general procedure I; flash
chromatography (EtOAc/hexane = 1:10, 50 mg, yield 91%), white
solid; m.p. 95−96 °C; [α]D28 = −6.26 (c = 0.40, CHCl3); 82% ee; H
1
NMR (400 MHz, CDCl3) δ 8.01−7.87 (m, 2H), 7.49−7.39 (m, 2H),
7.33−7.21 (m, 4H), 5.88 (td, J = 5.1, 2.4 Hz, 1H), 5.23−5.03 (m,
2H), 3.50 (dd, J = 16.5, 7.5 Hz, 1H), 3.31 (dd, J = 16.5, 4.9 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 196.8, 141.3, 139.9, 139.3, 135.5,
129.9, 129.1, 128.0, 127.6, 121.6, 121.2, 80.3, 72.8, 45.7; IR (neat)
2957, 2926, 2855, 1754, 1729, 1680, 1612, 1582, 1503, 1485, 1434,
1427, 1321, 1281, 1212, 1179, 1121, 1084, 1032 cm−1; HRMS (EI)
m/z calcd for [M]+ C16H13ClO2: 272.0604, found: 272.0579;
Chiralpak OJ-H column and OJ-H guard column, 5% i-PrOH/
hexanes, 1.0 mL/min flow, λ = 254 nm, major-isomer tr = 23.0 min
and minor-isomer tr = 29.4 min.
(S)-2-(1,3-Dihydroisobenzofuran-1-yl)-1-(p-tolyl)ethan-1-one
(2b).4c Synthesized by the general procedure I; flash chromatography
(EtOAc/hexane = 1:10, 47 mg, yield 94%), white solid; m.p. 76−78
°C; [α]2D8 = −24.7 (c = 0.40, CHCl3); 90% ee; H NMR (400 MHz,
1
CDCl3) δ 7.89 (d, J = 8.2 Hz, 2H), 7.32−7.22 (m, 6H), 5.90 (td, J =
5.2, 2.6 Hz, 1H), 5.13 (dt, J = 26.2, 7.3 Hz, 2H), 3.52 (dd, J = 16.6, 7.3
Hz, 1H), 3.32 (dd, J = 16.6, 5.2 Hz, 1H), 2.41 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 197.6, 144.2, 141. 7, 139.4, 134.8, 129.4, 128.6,
127.9, 127.6, 121. 7, 121.1, 80.3, 72.8, 45.6, 21.8; IR (neat) 2949,
2891, 2869, 1675, 1606, 1574, 1494, 1477, 1434, 1403, 1369, 1333,
1285, 1220, 1180, 1066, 1041 cm−1; HRMS (EI) m/z calcd for [M]+
C17H16O2: 252.1150, found: 252.1144; Chiralpak OJ-H column and
OJ-H guard column, 5% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254
nm, major-isomer tr = 17.8 min and minor-isomer tr = 27.9 min.
(S)-2-(1,3-Dihydroisobenzofuran-1-yl)-1-(4-methoxyphenyl)-
ethan-1-one (2c).4c Synthesized by the general procedure I; flash
chromatography (EtOAc/hexane = 1:10, 49 mg, yield 91%), white
solid; m.p. 109−111 °C; [α]2D7 = −34.2 (c = 0.41, CHCl3); 91% ee; 1H
NMR (400 MHz, CDCl3) δ 8.02−7.93 (m, 2H), 7.31−7.22 (m, 4H),
6.99−6.87 (m, 2H), 5.89 (td, J = 5.2, 2.6 Hz, 1H), 5.20−5.02 (m,
2H), 3.87 (s, 3H), 3.50 (dd, J = 16.4, 7.3 Hz, 1H), 3.29 (dd, J = 16.4,
5.1 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 196.5, 163.7, 141.7,
139.4, 130.8, 130.4, 127.9, 127.6, 121.7, 121.1, 113.9, 80.5, 72.7, 55.6,
45.4; IR (neat) 2942, 2902, 2860, 1739, 1670, 1621, 1575, 1555, 1510,
1468, 1445, 1416, 1383, 1331, 1288. 1167, 1114, 1065 cm−1; HRMS
(EI) m/z calcd for [M]+ C17H16O3: 268.1099, found: 268.1117;
Chiralpak OJ-H column and OJ-H guard column, 10% i-PrOH/
hexanes, 1.0 mL/min flow, λ = 254 nm, major-isomer tr = 29.7 min
and minor-isomer tr = 44.5 min.
(S)-1-(3-Chlorophenyl)-2-(1,3-dihydroisobenzofuran-1-yl)ethan-
1-one (2g). Synthesized by the general procedure I; flash
chromatography (EtOAc/hexane = 1:10, 54 mg, yield 99%), colorless
gum; [α]2D4 = −3.12 (c = 0.40, CHCl3); 78% ee; 1H NMR (400 MHz,
CDCl3) δ 7.96 (t, J = 1.8 Hz, 1H), 7.90−7.82 (m, 1H), 7.54 (ddd, J =
8.0, 2.1, 1.1 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.32−7.23 (m, 4H),
5.88 (td, J = 5.1, 2.4 Hz, 1H), 5.12 (qd, J = 12.1, 1.8 Hz, 2H), 3.51
(dd, J = 16.6, 7.5 Hz, 1H), 3.32 (dd, J = 16.6, 4.9 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 196.8, 141.3, 139.3, 138.7, 135.1, 133.3,
130.1, 128.6, 128.0, 127.7, 126.5, 121.5, 121.2, 80.2, 72.8, 45.8; IR
(neat) 2954, 2903, 2855, 1723, 1683, 1591, 1571, 1471, 1462, 1423,
1362, 1318, 1286, 1259, 1199, 1106, 1070, 1037 cm−1; HRMS (EI)
m/z calcd for [M]+ C16H13ClO2: 272.0604, found: 272.0613;
Chiralpak OJ-H column and OJ-H guard column, 5% i-PrOH/
hexanes, 1.0 mL/min flow, λ = 254 nm, major-isomer tr = 23.5 min
and minor-isomer tr = 27.1 min.
(S)-2-(1,3-Dihydroisobenzofuran-1-yl)-1-(furan-2-yl)ethan-1-one
(2h).4c Synthesized by the general procedure I; flash chromatography
(EtOAc/hexane = 1:10, 45 mg, yield 99%), colorless gum; [α]D27
=
1
−25.4 (c = 0.41, CHCl3); 86% ee; H NMR (400 MHz, CDCl3) δ
7.59 (dd, J = 1.7, 0.7 Hz, 1H), 7.33−7.19 (m, 5H), 6.54 (dd, J = 3.6,
1.7 Hz, 1H), 5.93−5.77 (m, 1H), 3.38 (dd, J = 15.8, 7.8 Hz, 1H), 3.20
(dd, J = 15.8, 4.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
186.7, 153.0, 146.8, 141.3, 139.3, 128.0, 127.6, 121.5, 121.2, 117.9,
112.5, 80.2, 72.8, 45.7; IR (neat) 3131, 2904, 2855, 1667, 1567, 1464,
1393, 1364, 1318, 1304, 1235, 1194, 1158, 1107, 1085, 1040 cm−1;
HRMS (EI) m/z calcd for [M]+ C14H12O3: 228.0786, found:
228.0764; Chiralpak OJ-H column and OJ-H guard column, 5% i-
PrOH/hexanes, 1.0 mL/min flow, λ = 254 nm, major-isomer tr = 33.9
min and minor-isomer tr = 50.9 min.
(S)-2-(1,3-Dihydroisobenzofuran-1-yl)-1-(4-fluorophenyl)ethan-
1-one (2d).4c Synthesized by the general procedure I; flash
chromatography (EtOAc/hexane = 1:10, 49 mg, yield 95%), white
solid; m.p. 69−71 °C; [α]D27 = +27.8 (c = 0.40, CHCl3); 87% ee; H
1
NMR (400 MHz, CDCl3) δ 8.08−7.98 (m, 2H), 7.32−7.23 (m, 4H),
7.18−7.09 (m, 2H), 5.88 (ddd, J = 7.3, 4.8, 2.1 Hz, 1H), 5.12 (qd, J =
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Article
(S)-2-(1,3-Dihydroisobenzofuran-1-yl)-1-(thiophen-2-yl)ethan-1-
one (2i).4c Synthesized by the general procedure I; flash
chromatography (EtOAc/hexane = 1:10, 48 mg, yield 98%), white
solid; m.p. 80−81 °C; [α]D27 = −16.9 (c = 0.2140, CHCl3); 89% ee; 1H
NMR (400 MHz, CDCl3) δ 7.73 (dd, J = 3.8, 1.1 Hz, 1H), 7.66 (dd, J
= 4.9, 1.1 Hz, 1H), 7.31−7.22 (m, 4H), 7.13 (dd, J = 4.9, 3.8 Hz, 1H),
5.87 (td, J = 5.3, 2.5 Hz, 1H), 5.14 (dt, J = 30.6, 7.2 Hz, 2H), 3.46 (dd,
J = 15.8, 7.6 Hz, 1H), 3.27 (dd, J = 15.8, 5.0 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 190.7, 144.7, 141.3, 139.3, 134.2, 132.7, 128.3,
128.0, 127.6, 121.6, 121.2, 80.4, 72.8, 46.5; IR (neat) 3090, 2901,
2853, 1651, 1611, 1518, 1478, 1413, 1355, 1317, 1299, 1286, 1234,
1215, 1168, 1106, 1030 cm−1; HRMS (EI) m/z calcd for [M]+
C14H12O2S: 244.0558, found: 244.0532; Chiralpak OJ-H column and
OJ-H guard column, 5% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254
nm, major-isomer tr = 32.3 min and minor-isomer tr = 38.4 min.
(S)-2-(5-Methyl-1,3-dihydroisobenzofuran-1-yl)-1-phenylethan-
1-one (2j). Synthesized by the general procedure I; flash
chromatography (EtOAc/hexane = 1:10, 33 mg, yield 66%), white
CDCl3) δ 197.7, 141.9, 140.8, 137.0, 133.5, 130.7, 128.8, 128.4, 124.5,
123.4, 121.8, 80.1, 72.2, 45.5; IR (neat) 3085, 2897, 2870, 1683, 1597,
1578, 1470, 1448, 1420, 1401, 1353, 1325, 1299, 1272, 1178, 1117,
1046 cm−1; HRMS (EI) m/z calcd for [M]+ C16H13BrO2: 316.0099,
found: 316.0085; Chiralpak OJ-H column and OJ-H guard column,
5% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254 nm, major-isomer tr =
30.1 min and minor-isomer tr = 49.9 min.
(S)-2-(6-Bromo-1,3-dihydroisobenzofuran-1-yl)-1-phenylethan-
1-one (2n). Synthesized by the general procedure I; flash
chromatography (EtOAc/hexane = 1:10, 61 mg, yield 96%), white
solid; m.p. 150−151 °C; [α]2D1 = −13.4 (c = 0.41, CHCl3); 94% ee; 1H
NMR (400 MHz, CDCl3) δ 7.98 (dd, J = 5.2, 3.3 Hz, 2H), 7.64−7.54
(m, 1H), 7.52−7.44 (m, 2H), 7.42 (d, J = 6.1 Hz, 2H), 7.15−7.06 (m,
1H), 5.87 (t, J = 6.0 Hz, 1H), 5.07 (dt, J = 25.3, 7.3 Hz, 2H), 3.56 (dd,
J = 17.0, 6.9 Hz, 1H), 3.34 (dd, J = 17.0, 5.5 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 197.5, 144.1, 138.5, 137.0, 133.5, 131.0, 128.8,
128.4, 125.1, 122.7, 121.4, 79.9, 72.5, 45.5; IR (neat) 3055, 2901,
2871, 1681, 1645, 1595, 1577, 1467, 1447, 1404, 1354, 1322, 1300,
1284, 1200, 1179, 1068, 1042 cm−1; HRMS (EI) m/z calcd for [M]+
C16H13BrO2: 316.0099, found: 316.0105; Chiralpak OJ-H column and
OJ-H guard column, 3% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254
nm, minor-isomer tr = 39.9 min and major-isomer tr = 42.6 min.
(S)-2-(6-Chloro-1,3-dihydroisobenzofuran-1-yl)-1-phenylethan-
1-one (2o). Synthesized by the general procedure I; flash
chromatography (EtOAc/hexane = 1:10, 54 mg, yield 99%), white
solid; m.p. 123−125 °C; [α]2D5 = −39.2 (c = 0.41, CHCl3); 92% ee; 1H
NMR (400 MHz, CDCl3) δ 8.03−7.95 (m, 2H), 7.63−7.56 (m, 1H),
7.52−7.44 (m, 2H), 7.26 (s, 2H), 7.20−7.12 (m, 1H), 5.87 (t, J = 6.1
Hz, 1H), 5.09 (dt, J = 24.9, 7.4 Hz, 2H), 3.56 (dd, J = 17.0, 6.9 Hz,
1H), 3.34 (dd, J = 17.0, 5.5 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 197.6, 143.8, 137.9, 137.0, 133.5, 133.5, 128.8, 128.4, 128.2,
122.3, 122.2, 79.9, 72.4, 45.5; IR (neat) 3046, 2902, 2873, 1681, 1644,
1579, 1553, 1470, 1447, 1403, 1383, 1323, 1314, 1285, 1203, 1177,
1076, 1044 cm−1; HRMS (EI) m/z calcd for [M]+ C16H13ClO2:
272.0604, found: 272.0607; Chiralpak IC column and IC guard
column, 5% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254 nm, major-
isomer tr = 19.8 min and major-isomer tr = 37.7 min.
(S)-2-(6-Fluoro-1,3-dihydroisobenzofuran-1-yl)-1-phenylethan-
1-one (2p). Synthesized by the general procedure I; flash
chromatography (EtOAc/hexane = 1:10, 37 mg, yield 73%), white
solid; m.p. 109−111 °C; [α]2D7 = −81.9 (c = 0.40, CHCl3); 83% ee; 1H
NMR (400 MHz, CDCl3) δ 8.07−7.93 (m, 2H), 7.64−7.54 (m, 1H),
7.53−7.43 (m, 2H), 7.21−7.11 (m, 1H), 6.99 (dd, J = 12.7, 5.6 Hz,
2H), 5.87 (t, J = 6.2 Hz, 1H), 5.16−4.97 (m, 2H), 3.57 (dd, J = 16.9,
6.8 Hz, 1H), 3.34 (dd, J = 16.9, 5.7 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 197.7, 162.8 (d, J = 244.7 Hz), 143.9 (d, J = 8.2 Hz),
137.0, 134.72 (d, J = 2.3 Hz), 133.5, 128.8, 128.4, 122.29 (d, J = 8.9
Hz), 115.09 (d, J = 23.1 Hz), 109.2 (d, J = 23.9 Hz), 80.1 (d, J = 2.7
Hz), 72.3, 45.5; IR (neat) 2903, 2875, 1674, 1613, 1597, 1580, 1502,
1483, 1448, 1402, 1326, 1285, 1208, 1160, 1135, 1077, 1046 cm−1;
HRMS (EI) m/z calcd for [M]+ C16H13FO2: 256.0900, found:
256.0912; Chiralpak OD-H column and OD-H guard column, 1% i-
PrOH/hexanes, 1.0 mL/min flow, λ = 254 nm, minor-isomer tr = 28.7
min and major-isomer tr = 31.4 min.
1
solid; m.p. 77−79 °C; [α]D21 = −5.11 (c = 0.40, CHCl3); 83% ee; H
NMR (400 MHz, CDCl3) δ 7.99 (dt, J = 8.5, 1.6 Hz, 2H), 7.62−7.53
(m, 1H), 7.53−7.40 (m, 2H), 7.19−7.01 (m, 3H), 5.86 (d, J = 5.4 Hz,
1H), 5.09 (dt, J = 24.9, 7.3 Hz, 2H), 3.52 (dd, J = 16.6, 7.3 Hz, 1H),
3.33 (dd, J = 16.6, 5.1 Hz, 1H), 2.37 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 198.1, 139.7, 138.8, 137.8, 137.2, 133.4, 128.7, 128.4
(two peaks overlapped), 121.7, 121.4, 80.2, 72.7, 45.9, 21.4; IR (neat)
2950, 2901, 2870, 1681, 1643, 1595, 1581, 1489, 1463, 1595, 1536,
1502, 1468, 1450, 1402, 1381, 1298, 1264, 1181, 1063 cm−1; HRMS
(EI) m/z calcd for [M]+ C17H16O2: 252.1150, found: 252.1144;
Chiralpak OJ-H column and OJ-H guard column, 5% i-PrOH/
hexanes, 1.0 mL/min flow, λ = 254 nm, major-isomer tr = 19.6 min
and minor-isomer tr = 30.2 min.
(S)-2-(6-Methyl-1,3-dihydroisobenzofuran-1-yl)-1-phenylethan-
1-one (2k).4c Synthesized by the general procedure I; flash
chromatography (EtOAc/hexane = 1:10, 46 mg, yield 92%), white
solid; m.p. 114−116 °C; [α]2D5 = −47.1 (c = 0.40, CHCl3); 89% ee; 1H
NMR (400 MHz, CDCl3) δ 8.00 (dt, J = 8.5, 1.6 Hz, 2H), 7.63−7.53
(m, 1H), 7.53−7.41 (m, 2H), 7.16−7.01 (m, 3H), 5.86 (td, J = 5.2,
2.6 Hz, 1H), 5.10 (dt, J = 25.3, 7.0 Hz, 2H), 3.53 (dd, J = 16.7, 7.3 Hz,
1H), 3.34 (dd, J = 16.7, 5.0 Hz, 1H), 2.36 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 198.1, 141.9, 137.4, 137.2, 136.5, 133.4, 128.8,
128.7, 128.4, 122.2, 120.9, 80.1, 72.7, 45.8, 21.5; IR (neat) 3056, 2902,
2870, 1682, 1596, 1576, 1492, 1447, 1405, 1356, 1291, 1259, 1202,
1179, 1109, 1046 cm−1; HRMS (EI) m/z calcd for [M]+ C17H16O2:
252.1150, found: 252.1142; Chiralpak OJ-H column and OJ-H guard
column, 5% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254 nm, major-
isomer tr = 18.0 min and minor-isomer tr = 22.4 min.
(S)-2-(4-Methoxy-1,3-dihydroisobenzofuran-1-yl)-1-phenyle-
than-1-one (2l). Synthesized by the general procedure I; flash
chromatography (EtOAc/hexane = 1:10, 53 mg, yield 98%), white
1
solid; m.p. 79−81 °C; [α]D21 = −2.22 (c = 0.40, CHCl3); 87% ee; H
NMR (400 MHz, CDCl3) δ 7.99 (dt, J = 8.5, 1.6 Hz, 2H), 7.62−7.54
(m, 1H), 7.50−7.42 (m, 2H), 7.25 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 7.5
Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 5.91 (td, J = 4.9, 2.2 Hz, 1H), 5.11
(ddd, J = 13.9, 12.5, 2.2 Hz, 2H), 3.84 (s, 3H), 3.53 (dd, J = 16.6, 7.4
Hz, 1H), 3.33 (dd, J = 16.6, 5.0 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 197.9, 154.2, 143.6, 137.2, 133.4, 129.5, 128.7, 128.4, 127.2,
113.7, 109.4, 80.8, 71.3, 55.4, 45.8; IR (neat) 2938, 2901, 2839, 1680,
1613, 1597, 1581, 1485, 1471, 1448, 1362, 1313, 1287, 1264, 1208,
1181, 1099, 1035 cm−1; HRMS (EI) m/z calcd for [M]+ C17H16O3:
268.1099, found: 268.1107; Chiralpak OJ-H column and OJ-H guard
column, 5% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254 nm, major-
isomer tr = 29.8 min and minor-isomer tr = 34.8 min.
(S)-1-Phenyl-2-(6-(trifluoromethyl)-1,3-dihydroisobenzofuran-1-
yl)ethan-1-one (2q). Synthesized by the general procedure I; flash
chromatography (EtOAc/hexane = 1:10, 58 mg, yield 94%), white
solid; m.p. 109−110 °C; [α]2D4 = −1.37 (c = 0.41, CHCl3); 87% ee; 1H
NMR (400 MHz, CDCl3) δ 8.00 (dt, J = 8.5, 1.6 Hz, 2H), 7.64−7.53
(m, 3H), 7.51−7.46 (m, 2H), 7.35 (d, J = 7.9 Hz, 1H), 5.94 (t, J = 6.1
Hz, 1H), 5.16 (q, J = 12.9 Hz, 2H), 3.59 (dd, J = 17.0, 6.9 Hz, 1H),
3.39 (dd, J = 17.0, 5.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
197.4, 143.5, 142.6, 136.9, 133.6, 130.4 (q, J2 = 32.2 Hz), 128.8, 128.4,
125.3 (q, J3 = 3.7 Hz), 124.3 (d, J1 = 272.3 Hz), 121.6, 119.0 (q, J3 =
3.8 Hz), 80.0, 72.5, 45.4; IR (neat) 3068. 2909, 2868, 1695, 1624,
1596, 1489, 1462, 1448, 1408, 1371, 1357, 1285, 1257, 1206, 1180,
1126, 1065, 1043 cm−1; HRMS (EI) m/z calcd for [M]+ C17H13F3O2:
306.0868, found: 306.0878; Chiralpak IC column and IC guard
column, 5% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254 nm, major-
isomer tr = 14.1 min and minor-isomer tr = 30.1 min.
(S)-2-(5-Bromo-1,3-dihydroisobenzofuran-1-yl)-1-phenylethan-
1-one (2m). Synthesized by the general procedure I; flash
chromatography (EtOAc/hexane = 1:10, 61 mg, yield 97%), white
solid; m.p. 109−111 °C; [α]2D5 = −5.47 (c = 0.40, CHCl3); 92% ee; 1H
NMR (400 MHz, CDCl3) δ 8.03−7.94 (m, 2H), 7.63−7.54 (m, 1H),
7.52−7.43 (m, 2H), 7.42−7.35 (m, 2H), 7.14 (d, J = 7.8 Hz, 1H), 5.84
(t, J = 6.2 Hz, 1H), 5.16−5.01 (m, 2H), 3.54 (dd, J = 16.8, 6.8 Hz,
1H), 3.33 (dd, J = 16.8, 5.6 Hz, 1H); 13C{1H} NMR (100 MHz,
6835
https://doi.org/10.1021/acs.joc.1c00715
J. Org. Chem. 2021, 86, 6826−6839

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
(S)-2-(6-Nitro-1,3-dihydroisobenzofuran-1-yl)-1-phenylethan-1-
one (2r). Synthesized by the general procedure I; flash chromatog-
raphy (EtOAc/hexane = 1:10, 54 mg, yield 96%), white solid; m.p.
−3.54 (c = 0.41, CHCl3); 85% ee; H NMR (400 MHz, CDCl3) δ
7.43−7.30 (m, 5H), 7.08−6.99 (m, 3H), 5.65 (t, J = 6.0 Hz, 1H),
5.24−5.14 (m, 2H), 5.08 (dt, J = 26.0, 7.4 Hz, 2H), 2.81 (qd, J = 15.6,
6.3 Hz, 2H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
170.8, 139.6, 137.9 (two peaks overlapped), 135.9, 128.7, 128.4,
128.41, 128.37, 121.7, 121.0, 80.3, 72.7, 66.6, 41.8, 21.4; IR (neat)
3033, 2952, 2917, 2860, 1731, 1620, 1494, 1455, 1382, 1356, 1296,
1282, 1214, 1154, 1037 cm−1; HRMS (EI) m/z calcd for [M]+
C18H18O3: 282.1256, found: 282.1266; Chiralpak OJ-H column and
OJ-H guard column, 3% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254
nm, major-isomer tr = 39.1 min and minor-isomer tr = 66.4 min.
Benzyl (S)-2-(6-Methyl-1,3-dihydroisobenzofuran-1-yl)acetate
(4e). Synthesized by the general procedure II; flash chromatography
197−199 °C; [α]2D5 = −6.99 (c = 0.40, CHCl3); 83% ee; H NMR
1
(400 MHz, CDCl3) δ 8.21 (dd, J = 8.3, 1.8 Hz, 1H), 8.16 (s, 1H),
8.06−7.93 (m, 2H), 7.68−7.58 (m, 1H), 7.48 (dd, J = 10.5, 4.7 Hz,
2H), 7.39 (d, J = 8.2 Hz, 1H), 5.95 (d, J = 5.8 Hz, 1H), 5.26−5.12 (m,
2H), 3.62 (dd, J = 17.2, 6.6 Hz, 1H), 3.44 (dd, J = 17.2, 5.7 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 197.1, 148.3, 146.8, 143.7, 136.8,
133.7, 128.9, 128.4, 123.9, 121.9, 117.6, 79.9, 72.4, 45.1; IR (neat)
2956, 2921, 2853, 1730, 1672, 1593, 1575,, 1516, 1445, 1407, 1342,
1323, 1285, 1250, 1206, 1174, 1125, 1081, 1046 cm−1; HRMS (EI)
m/z calcd for [M]+ C16H13NO4: 283.0845, found: 283.0863;
Chiralpak OJ-H column and OJ-H guard column, 10% i-PrOH/
hexanes, 1.0 mL/min flow, λ = 254 nm, major-isomer tr = 120 min and
minor-isomer tr = 139 min.
(EtOAc/hexane = 1:5, 46 mg, yield 82%), colorless gum; [α]D20
=
1
−7.16 (c = 0.40, CHCl3); 84% ee; H NMR (400 MHz, CDCl3) δ
7.42−7.30 (m, 5H), 7.10 (s, 2H), 6.95 (s, 1H), 5.65 (td, J = 5.2, 2.6
Hz, 1H), 5.23−5.14 (m, 2H), 5.08 (dt, J = 26.4, 7.2 Hz, 2H), 2.89−
2.74 (m, 2H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
170.8, 141.0, 137.4, 136.4, 135.9, 128.9, 128.7, 128.4, 128.4, 121.8,
120.9, 80.3, 72.7, 66.6, 41.8, 21.4; IR (neat) 3033, 2953, 2918, 2859,
1731, 1620, 1495, 1455, 1382, 1360, 1290, 1259, 1216, 1153, 1037
cm−1; HRMS (EI) m/z calcd for [M]+ C18H18O3: 282.1256, found:
282.1248; Chiralpak OJ-H column and OJ-H guard column, 3% i-
PrOH/hexanes, 1.0 mL/min flow, λ = 254 nm, major-isomer tr = 35.4
min and minor-isomer tr = 58.0 min.
General Procedure II for Asymmetric Intramolecular Oxa-
Michael Reaction of β-(2-(Hydroxymethyl)phenyl) α,β-Unsa-
turated Esters. To a solution of β-(2-(hydroxymethyl)phenyl) α,β-
unsaturated ester 3 (0.20 mmol, 1.0 equiv) in trifluorotoluene (0.4
mL) was added catalyst IVd (0.010 mmol, 0.05 equiv) at room
temperature. The reaction mixture was allowed to stir at 50 °C in an
oil bath until β-(2-(hydroxymethyl)phenyl) α,β-unsaturated ketone 3
was completely consumed, as determined by TLC. Then, the reaction
was cooled to room temperature and diluted with EtOAc/hexane
(1:1). The resulting mixture was filtered through a plug of celite and
concentrated in vacuo. The crude residue was purified by flash column
chromatography with EtOAc/hexane as an eluent to afford the desired
product 4.
Benzyl (S)-2-(4-methoxy-1,3-dihydroisobenzofuran-1-yl)acetate
(4f). Synthesized by the general procedure II; flash chromatography
(EtOAc/hexane = 1:5, 59 mg, yield 99%), colorless gum; [α]D26
=
1
−3.13 (c = 0.40, CHCl3); 87% ee; H NMR (400 MHz, CDCl3) δ
7.41−7.29 (m, 5H), 7.23 (t, J = 7.8 Hz, 1H), 6.75 (t, J = 8.2 Hz, 2H),
5.69 (td, J = 5.1, 2.3 Hz, 1H), 5.24−5.02 (m, 4H), 3.83 (s, 3H), 2.90−
2.74 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 154.2,
142.7, 135.9, 129.5, 128.7, 128.4, 128.4, 127.1, 113.4, 109.5, 80.9, 71.5,
66.6, 55.4, 41.8; IR (neat) 3033, 2939, 2904, 2840, 1731, 1614, 1598,
1486, 1440, 1410, 1383, 1360, 1315, 1288, 1263, 1152, 1100, 1034
cm−1; HRMS (EI) m/z calcd for [M]+ C18H18O4: 298.1205, found:
298.1212; Chiralpak OJ-H column and OJ-H guard column, 5% i-
PrOH/hexanes, 1.0 mL/min flow, λ = 254 nm, major-isomer tr = 44.2
min and minor-isomer tr = 51.6 min.
Methyl (S)-2-(1,3-Dihydroisobenzofuran-1-yl)acetate (4a).4d
Synthesized by the general procedure II; flash chromatography
(EtOAc/hexane = 1:5, 27 mg, yield 70%), colorless gum; [α]D24
=
1
−2.81 (c = 0.40, CHCl3); 81% ee; H NMR (400 MHz, CDCl3) δ
7.35−7.17 (m, 4H), 5.71−5.62 (m, 1H), 5.14 (ddd, J = 31.4, 16.8, 7.2
Hz, 2H), 3.75 (s, 3H), 2.78 (qd, J = 15.6, 6.4 Hz, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 171.4, 140.7, 139.3, 128.0, 127.6, 121.3, 121.2,
80.4, 72.9, 52.0, 41.6; IR (neat) 2952, 2909, 2851, 1732, 1650, 1493,
1479, 1461, 1435, 1414, 1366, 1319, 1299, 1285, 1259, 1219, 1191,
1160, 1108, 1036 cm−1; HRMS (EI) m/z calcd for [M]+ C11H12O3:
192.0786, found: 192.0801; Chiralpak OJ-H column and OJ-H guard
column, 2% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254 nm, major-
isomer tr = 21.0 min and minor-isomer tr = 23.7 min.
Benzyl (S)-2-(4-Bromo-1,3-dihydroisobenzofuran-1-yl)acetate
(4g). Synthesized by the general procedure II; flash chromatography
(EtOAc/hexane = 1:5, 60 mg, yield 87%), colorless gum; [α]D20
=
1
Ethyl (S)-2-(1,3-Dihydroisobenzofuran-1-yl)acetate (4b). Synthe-
sized by the general procedure II; flash chromatography (EtOAc/
hexane = 1:5, 33 mg, yield 79%), colorless gum; [α]2D6 = −35.8(c =
0.40, CHCl3); 81% ee; 1H NMR (400 MHz, CDCl3) δ 7.36−7.17 (m,
4H), 5.74−5.61 (m, 1H), 5.13 (dt, J = 31.6, 7.2 Hz, 2H), 4.20 (q, J =
7.1 Hz, 2H), 2.77 (qd, J = 15.6, 6.4 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 171.0, 140.8, 139.3, 128.0, 127.6,
121.3, 121.2, 80.5, 72.9, 60.9, 41.8, 14.3; IR (neat) 2980, 2924, 2855,
1730, 1633, 1612, 1462, 1393, 1372, 1318, 1299, 1287, 1258, 1217,
1159, 1109, 1035 cm−1; HRMS (EI) m/z calcd for [M]+ C12H14O3:
206.0943, found: 206.0943; Chiralpak OJ-H column and OJ-H guard
column, 5% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254 nm, major-
isomer tr = 12.4 min and minor-isomer tr = 15.9 min.
+1.16 (c = 0.41, CHCl3); 84% ee; H NMR (400 MHz, CDCl3) δ
7.45−7.29 (m, 6H), 7.13 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H),
5.76 (t, J = 5.9 Hz, 1H), 5.19 (d, J = 12.6 Hz, 2H), 5.07 (dt, J = 22.3,
7.8 Hz, 2H), 2.83 (d, J = 6.3 Hz, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 170.4, 142.7, 140.0, 135.8, 131.0, 129.6, 128.7, 128.5 (two
peak overlapped), 120.2, 116.0, 81.6, 74.0, 66.7, 41.6; IR (neat) 3033,
2952, 2917, 2853, 1730, 1608, 1498, 1453, 1383, 1360, 1309, 1295,
1281, 1257, 1228, 1155, 1132, 1038 cm−1; HRMS (EI) m/z calcd for
[M]+ C17H15BrO3: 346.0205, found: 346.0202; Chiralpak OJ-H
column and OJ-H guard column, 5% i-PrOH/hexanes, 1.0 mL/min
flow, λ = 254 nm, major-isomer tr = 27.6 min and minor-isomer tr =
36.3 min.
Benzyl (S)-2-(5-Bromo-1,3-dihydroisobenzofuran-1-yl)acetate
(4h). Synthesized by the general procedure II; flash chromatography
Benzyl (S)-2-(1,3-Dihydroisobenzofuran-1-yl)acetate (4c). Syn-
thesized by the general procedure II; flash chromatography (EtOAc/
hexane = 1:5, 55 mg, yield 81%), colorless gum; [α]2D7 = −30.5 (c =
0.40, CHCl3); 85% ee; 1H NMR (400 MHz, CDCl3) δ 7.40−7.09 (m,
9H), 5.77−5.63 (m, 1H), 5.25−5.03 (m, 4H), 2.83 (qd, J = 15.6, 6.3
Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 140.7, 139.3,
135.9, 128.7, 128.5, 128.4, 128.0, 127.6, 121.3, 121.2, 80.4, 72.9, 66.6,
41.7; IR (neat) 3329, 2922, 2851, 1677, 1495, 1454, 1380, 1359, 1291,
1273, 1260, 1190, 1113, 1030 cm−1; HRMS (EI) m/z calcd for [M]+
C17H16O3: 269.1099, found: 268.1085; Chiralpak OJ-H column and
OJ-H guard column, 5% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254
nm, major-isomer tr = 24.2 min and minor-isomer tr = 31.4 min.
Benzyl (S)-2-(5-Methyl-1,3-dihydroisobenzofuran-1-yl)acetate
(4d). Synthesized by the general procedure II; flash chromatography
(EtOAc/hexane = 1:5, 59 mg, yield 85%), colorless gum; [α]D20
=
1
−3.15 (c = 0.41, CHCl3); 85% ee; H NMR (400 MHz, CDCl3) δ
7.44−7.29 (m, 7H), 7.01 (d, J = 7.9 Hz, 1H), 5.61 (t, J = 5.5 Hz, 1H),
5.17 (s, 2H), 5.05 (q, J = 12.6 Hz, 2H), 2.81 (d, J = 6.6 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 170.4, 141.8, 139.8, 135.7, 130.7,
128.7, 128.50, 128.47, 124.6, 122.9, 121.9, 80.1, 72.3, 66.7, 41.4; IR
(neat) 3033, 2953, 2917, 2858, 1730, 1603, 1583, 1498, 1471, 1455,
1412, 1383, 1354, 1312, 1294, 1254, 1212, 1153, 1062, 1037 cm−1;
HRMS (EI) m/z calcd for [M]+ C17H15BrO3: 346.0205, found:
346.0208; Chiralpak IA column and IA guard column, 2% i-PrOH/
hexanes, 1.0 mL/min flow, λ = 254 nm, minor-isomer tr = 16.8 min
and minor-isomer tr = 19.2 min.
Benzyl (S)-2-(6-bromo-1,3-dihydroisobenzofuran-1-yl)acetate
(4i). Synthesized by the general procedure II; flash chromatography
(EtOAc/hexane = 1:5, 45 mg, yield 80%), colorless gum; [α]D20
=
6836
https://doi.org/10.1021/acs.joc.1c00715
J. Org. Chem. 2021, 86, 6826−6839

The Journal of Organic Chemistry
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Article
(EtOAc/hexane = 1:5, 62 mg, yield 90%), colorless gum; [α]D20
=
5% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254 nm, minor-isomer tr =
50.2 min and major-isomer tr = 71.3 min.
1
−7.72 (c = 0.40, CHCl3); 85% ee; H NMR (400 MHz, CDCl3) δ
7.45−7.29 (m, 7H), 7.08 (d, J = 8.0 Hz, 1H), 5.64 (t, J = 6.1 Hz, 1H),
5.18 (s, 2H), 5.05 (dt, J = 25.4, 7.4 Hz, 2H), 2.82 (dd, J = 6.3, 1.6 Hz,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.4, 143.2, 138.4, 135.7,
131.1, 128.7, 128.5 (two peak overlapped), 124.7, 122.8, 121.3, 80.0,
72.6, 66.8, 41.4; IR (neat) 3033, 2954, 2917, 2855, 1730, 1604, 1584,
1498, 1470, 1455, 1410, 1384, 1359, 1309, 1277, 1253, 1215, 1154,
1064 cm−1; HRMS (EI) m/z calcd for [M]+ C17H15BrO3: 346.0205,
found: 346.0197; Chiralpak OJ-H column and OJ-H guard column,
20% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254 nm, major-isomer tr
= 27.5 min and minor-isomer tr = 30.5 min.
Ethyl (S)-2-(4-Methoxy-1,3-dihydroisobenzofuran-1-yl)acetate
(4n). Synthesized by the general procedure I; flash chromatography
(EtOAc/hexane = 1:5, 46 mg, yield 97%), colorless gum; [α]D20
=
1
−5.30 (c = 0.40, CHCl3); 85% ee; H NMR (400 MHz, CDCl3) δ
7.26 (t, J = 3.9 Hz, 1H), 6.78 (d, J = 4.6 Hz, 1H), 6.76 (d, J = 5.2 Hz,
1H), 5.74−5.59 (m, 1H), 5.12 (dt, J = 32.0, 7.6 Hz, 2H), 4.20 (q, J =
7.1 Hz, 2H), 3.83 (s, 3H), 2.75 (qd, J = 15.6, 6.4 Hz, 2H), 1.27 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.0, 154.2, 142.8,
129.5, 127.1, 113.4, 109.4, 81.0, 71.4, 60.8, 55.4, 41.8, 14.3; IR (neat)
2979, 2939, 2840, 1730, 1614, 1599, 1486, 1472, 1441, 1410, 1314,
1289, 1263, 1231, 1158, 1097, 1035 cm−1; HRMS (EI) m/z calcd for
[M]+ C13H16O4: 236.1049, found: 236.1054; Chiralpak OJ-H column
and OJ-H guard column, 5% i-PrOH/hexanes, 1.0 mL/min flow, λ =
254 nm, major-isomer tr = 16.1 min and minor-isomer tr = 18.7 min.
Ethyl (S)-2-(4-Bromo-1,3-dihydroisobenzofuran-1-yl)acetate
(4o).4d Synthesized by the general procedure I; flash chromatography
Benzyl (S)-2-(5-Chloro-1,3-dihydroisobenzofuran-1-yl)acetate
(4j). Synthesized by the general procedure II; flash chromatography
(EtOAc/hexane = 1:5, 57 mg, yield 94%), colorless gum; [α]D20
=
1
−1.06 (c = 0.37, CHCl3); 86% ee; H NMR (400 MHz, CDCl3) δ
7.45−7.29 (m, 5H), 7.25−7.15 (m, 2H), 7.06 (d, J = 8.0 Hz, 1H), 5.63
(t, J = 6.2 Hz, 1H), 5.17 (s, 2H), 5.12−4.98 (m, 2H), 2.82 (dd, J = 6.3,
1.2 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.5, 141.4, 139.3,
135.8, 133.97, 128.7, 128.50, 128.47, 127.9, 122.5, 121.6, 80.1, 72.4,
66.7, 41.5; IR (neat) 3032, 2952, 2918, 2858, 1730, 1607, 1586, 1498,
1475, 1455, 1416, 1383, 1355, 1312, 1295, 1254, 1154, 1073, 1038
cm−1; HRMS (EI) m/z calcd for [M]+ C17H15ClO3: 302.0710, found:
302.0705; Chiralpak IA column and IA guard column, 3% EtOH/
hexanes, 0.5 mL/min flow, λ = 254 nm, minor-isomer tr = 14.1 min
and major-isomer tr = 16.0 min.
(EtOAc/hexane = 1:5, 56 mg, yield 98%), colorless gum; [α]D20
=
1
+9.73 (c = 0.41, CHCl3); 79% ee; H NMR (400 MHz, CDCl3) δ 7
7.41 (d, J = 7.2 Hz, 1H), 7.20−7.10 (m, 2H), 5.81−5.71 (m, 1H), 5.08
(ddd, J = 14.2, 13.0, 2.0 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 2.84−2.72
(m, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 170.6, 142.8, 140.0, 131.02, 129.6, 120.2, 116.0, 81.6, 74.0, 60.9,
41.7, 14.3; IR (neat) 2980, 2906, 2854, 1730, 1608, 1577, 1451, 1373,
1309, 1281, 1254, 1228, 1162, 1133, 1096, 1049 cm−1; HRMS (EI)
m/z calcd for [M]+ C12H13BrO3: 284.0048, found: 284.0031;
Chiralpak OJ-H column and OJ-H guard column, 5% i-PrOH/
hexanes, 1.0 mL/min flow, λ = 254 nm, major-isomer tr = 10.5 min
and minor-isomer tr = 13.5 min.
Benzyl (S)-2-(6-Chloro-1,3-dihydroisobenzofuran-1-yl)acetate
(4k). Synthesized by the general procedure II; flash chromatography
(EtOAc/hexane = 1:5, 52 mg, yield 85%), colorless gum; [α]D20
=
1
−7.50 (c = 0.41, CHCl3); 80% ee; H NMR (400 MHz, CDCl3) δ
7.42−7.32 (m, 5H), 7.27−7.24 (m, 1H), 7.18−7.11 (m, 2H), 5.64 (t, J
= 6.1 Hz, 1H), 5.18 (s, 2H), 5.06 (dt, J = 24.9, 7.4 Hz, 2H), 2.87−2.79
(m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.4, 142.8, 137.9,
135.8, 133.5, 128.7, 128.5 (two peak overlapped), 128.3, 122.4, 121.8,
80.1, 72.5, 66.8, 41.4; IR (neat) 3034, 2954, 2921, 2855, 1731, 1607,
1586, 1497, 1474, 1455, 1415, 1383, 1359, 1310, 1278, 1253, 1216,
1154, 1078, 1038 cm−1; HRMS (EI) m/z calcd for [M]+ C17H15ClO3:
302.0710, found: 302.0708; Chiralpak OJ-H column and OJ-H guard
column, 5% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254 nm, major-
isomer tr = 39.6 min and minor-isomer tr = 44.9 min.
Ethyl (S)-2-(5-Bromo-1,3-dihydroisobenzofuran-1-yl)acetate
(4p). Synthesized by the general procedure I; flash chromatography
(EtOAc/hexane = 1:5, 50 mg, yield 88%), colorless gum; [α]D20
=
1
−2.05 (c = 0.41, CHCl3); 80% ee; H NMR (400 MHz, CDCl3) δ
7.45−7.34 (m, 2H), 7.07 (d, J = 8.0 Hz, 1H), 5.60 (dd, J = 6.8, 5.7 Hz,
1H), 5.09 (dt, J = 30.3, 7.5 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 2.75
(dd, J = 6.3, 2.6 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 170.7, 141.8, 140.0, 130.7, 124.5, 122.9, 121.9,
80.2, 72.3, 60.9, 41.5, 14.3; IR (neat) 2980, 2906, 2858, 1728, 1603,
1581, 1471, 1446, 1412, 1373, 1352, 1296, 1268, 1252, 1211, 1159,
1062, 1036 cm−1; HRMS (EI) m/z calcd for [M]+ C12H13BrO3:
284.0048, found: 284.0031; Chiralpak OJ-H column and OJ-H guard
column, 5% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254 nm, major-
isomer tr = 16.9 min and minor-isomer tr = 33.0 min.
Benzyl (S)-2-(6-Fluoro-1,3-dihydroisobenzofuran-1-yl)acetate
(4l). Synthesized by the general procedure II; flash chromatography
(EtOAc/hexane = 1:5, 53 mg, yield 93%), colorless gum; [α]D20
=
1
−1.81 (c = 0.40, CHCl3); 86% ee; H NMR (400 MHz, CDCl3) δ
7.42−7.29 (m, 5H), 7.15 (dd, J = 8.3, 4.8 Hz, 1H), 6.98 (td, J = 8.5,
2.2 Hz, 1H), 6.85 (dd, J = 8.4, 2.1 Hz, 1H), 5.65 (t, J = 6.3 Hz, 1H),
5.18 (s, 2H), 5.05 (q, J = 12.3 Hz, 2H), 2.82 (d, J = 6.3 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 170.5, 135.77, 162.7 (d, J1 =
Ethyl (S)-2-(5-Chloro-1,3-dihydroisobenzofuran-1-yl)acetate
(4q). Synthesized by the general procedure I; flash chromatography
(EtOAc/hexane = 1:5, 44 mg, yield 91%), colorless gum; [α]D20
=
1
244.9 Hz), 143.0 (d, J3 = 8.1 Hz), 134.7 (d, J4 = 2.3 Hz), 128.73, 128.5
(two peaks overlapped), 122.4 (d, J3 = 8.9 Hz), 115.2 (d, J2 = 23.1
Hz), 108.8 (d, J2 = 23.8 Hz), 80.2 (d, J4 = 2.7 Hz), 72.5, 66.7, 41.4; IR
(neat) 3034, 1730, 1615, 1603, 1488, 1455, 1436, 1384, 1364, 1311,
1283, 1254, 1245, 1216, 1155, 1104, 1038 cm−1; HRMS (EI) m/z
calcd for [M]+ C17H15FO3: 286.1005, found: 286.1013; Chiralpak OJ-
H column and OJ-H guard column, 5% i-PrOH/hexanes, 1.0 mL/min
flow, λ = 254 nm, major-isomer tr = 39.0 min and minor-isomer tr =
47.5 min.
Benzyl (S)-2-(6-(Trifluoromethyl)-1,3-dihydroisobenzofuran-1-
yl)acetate (4m). Synthesized by the general procedure II; flash
chromatography (EtOAc/hexane = 1:5, 62 mg, yield 93%), colorless
gum; [α]2D0 = −2.49 (c = 0.41, CHCl3); 86% ee; 1H NMR (400 MHz,
CDCl3) δ 7.56 (d, J = 7.9 Hz, 1H), 7.45 (s, 1H), 7.41−7.30 (m, 6H),
5.71 (t, J = 6.1 Hz, 1H), 5.24−5.06 (m, 4H), 2.97−2.79 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 170.3, 143.4, 141.7, 135.7, 130.4
−2.78 (c = 0.41, CHCl3); 80% ee; H NMR (400 MHz, CDCl3) δ
7.26−7.19 (m, 2H), 7.12 (d, J = 8.1 Hz, 1H), 5.67−5.58 (m, 1H), 5.09
(dt, J = 30.7, 7.5 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 2.75 (dd, J = 6.3,
2.9 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 170.7, 141.4, 139.4, 134.0, 127.87, 122.5, 121.6, 80.1, 72.4,
60.9, 41.6, 14.3; IR (neat) 2981, 2907, 2859, 1729, 1607, 1586, 1475,
1446, 1416, 1374, 1353, 1311, 1297, 1269, 1251, 1214, 1160, 1073,
1039 cm−1; HRMS (EI) m/z calcd for [M]+ C12H13ClO3: 240.0553,
found: 240.0532; Chiralpak OJ-H column and OJ-H guard column,
5% i-PrOH/hexanes, 1.0 mL/min flow, λ = 254 nm, major-isomer tr =
15.1 min and minor-isomer tr = 27.8 min.
Asymmetric Intramolecular Oxa-Michael Reaction of β-(2-
(Hydroxymethyl)phenyl) α,β-Unsaturated Methyl Ketone. To a
solution of β-(2-(hydroxymethyl)phenyl) α,β-unsaturated methyl
ketone 5 (35 mg, 0.20 mmol) in trifluorotoluene (0.4 mL) was
added catalyst IVd (6.4 mg, 0.010 mmol) at room temperature. The
reaction mixture was allowed to stir at room temperature until β-(2-
(hydroxymethyl)phenyl) α,β-unsaturated methyl ketone 5 was
completely consumed, as determined by TLC. Then, the reaction
was cooled to room temperature and diluted with EtOAc/hexane
(1:1). The resulting mixture was filtered through a plug of celite and
concentrated in vacuo. The crude residue was purified by flash column
(q, J2 = 32.4 Hz), 128.74, 128.49, 128.5, 125.4 (q, J3 = 3.7 Hz), 124.2
(q, J1 = 272.3 Hz), 121.7 (two peaks overlapped), 118.6 (q, J3 = 3.8
Hz), 80.1, 72.6, 66.8, 41.3; IR (neat) 3035, 2953, 2862, 1732, 1598,
1499, 1455, 1438, 1385, 1327, 1277, 1260, 1219, 1156, 1116, 1062,
1039 cm−1; HRMS (EI) m/z calcd for [M]+ C18H15F3O3: 336.0973,
found: 336.0970; Chiralpak OJ-H column and OJ-H guard column,
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pubs.acs.org/joc
Article
chromatography with (EtOAc/hexane = 1:10) as an eluent to afford
the desired product 6 (33 mg, yield 95%).
AUTHOR INFORMATION
Corresponding Author
■
(S)-1-(1,3-Dihydroisobenzofuran-1-yl)propan-2-one. Colorless
Sung-Gon Kim − Department of Chemistry, College of Natural
Science, Kyonggi University, Suwon 16227, Republic of
Korea; orcid.org/0000-0001-5099-0944;
Email: sgkim123@kyonggi.ac.kr
gum; [α]2D7 = −30.5 (c = 0.40, CHCl3); 78% ee; H NMR (400
1
MHz, CDCl3) δ 7.32−7.16 (m, 4H), 5.76−5.59 (m, 1H), 5.20−5.00
(m, 2H), 3.01−2.80 (m, 2H), 2.24 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 206.8, 141.2, 139.3, 127.9, 127.6, 121.3, 121.2, 80.0,
72.8, 50.5, 31.1; IR (neat) 3030, 2955, 2917, 2853, 1712, 1479, 1462,
1415, 1359, 1317, 1257, 1181, 1160, 1107, 1047 cm−1; HRMS (EI)
m/z calcd for [M]+ C11H12O2: 176.0837, found: 176.0847; Chiralpak
OJ-H column and OJ-H guard column, 2% i-PrOH/hexanes, 1.0 mL/
min flow, λ = 254 nm, major-isomer tr = 10.8 min and minor-isomer tr
= 89.2 min.
Authors
Eun Chae Son − Department of Chemistry, College of Natural
Science, Kyonggi University, Suwon 16227, Republic of Korea
Seung Yeon Kim − Department of Chemistry, College of
Natural Science, Kyonggi University, Suwon 16227, Republic
of Korea
Enantioselective Synthesis of 1,3-Dihydroisobenxofuran 2a
via Wittig/Oxa-Michael Reaction. To a solution of 1,3-dihydro-2-
benzofuran-1-ol 7 (27 mg, 0.20 mmol) and catalyst IVd (6.4 mg,
0.010 mmol) in CH2Cl2 (2 mL) was added triphenyl phosphonium
ylide 8 (114 mg, 0.30 mmol) at room temperature. The reaction
mixture was stirred at the same temperature for 72 h. Then, the
resulting mixture was filtered through a plug of celite and concentrated
in vacuo. The crude residue was purified by flash column
chromatography with (EtOAc/hexane = 1:10) as an eluent to afford
the desired product 2a (28 mg, 58%, 84% ee) as a white solid.
Procedure for a 1 mmol Scale Synthesis of 2a. To a solution
of β-(2-(hydroxymethyl)phenyl) α,β-unsaturated ketone 1a (238 mg,
1.0 mmol) in trifluorotoluene (2 mL) was added catalyst IVd (32 mg,
0.050 mmol) at room temperature. The reaction mixture was stirred at
the same temperature for 12 h. Then, the resulting mixture was diluted
with EtOAc/hexane (1:1), filtered through a plug of celite, and
concentrated in vacuo. The crude residue was purified by flash column
chromatography with (EtOAc/hexane = 1:10) as an eluent to afford
the desired product 2a (226 mg, 95% yield, 90% ee) as a white solid.
Procedure for the Functional Group Transformation. To a
solution of compound 4j (30 mg, 0.10 mmol) in THF (1 mL) was
added dropwise LiAlH4 (0.3 mL, 1 M in THF) at 0 °C. The reaction
mixture was allowed to stir at room temperature until compound 4j
was completely consumed (1 h), as determined by TLC. Then, the
reaction mixture was poured into a vigorously stirring solution of Et2O
and a saturated aqueous Rochelle’s salt solution. Et2O was added, and
the resulting biphasic mixture was stirred vigorously for 1 h. The
organic layer was extracted, washed with brine, dried over MgSO4, and
concentrated in vacuo. The crude residue was purified by flash column
chromatography with (EtOAc/hexane = 1:3) as an eluent to afford the
desired product 9 (18 mg, 92% yield).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00715
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by the National Research
Foundation of Korea (NRF-2020R1A2C1005438).
■
REFERENCES
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1
White solid; m.p. 53−55 °C; H NMR (400 MHz, CDCl3) δ 7.25
(ddd, J = 16.0, 6.5, 5.7 Hz, 2H), 7.08 (d, J = 8.0 Hz, 1H), 5.47−5.34
(m, 1H), 5.08 (dt, J = 32.1, 7.4 Hz, 2H), 3.95−3.76 (m, 2H), 2.50 (s,
1H), 2.13 (dddd, J = 14.3, 6.7, 4.3, 3.3 Hz, 1H), 1.92 (dddd, J = 14.5,
8.7, 7.2, 4.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 141.2,
140.2, 133.7, 127.9, 122.3, 121.6, 83.4, 72.2, 60.9, 37.9; IR (neat)
3276, 2923, 2895, 2863, 1738, 1607, 1585, 1476, 1462, 1440, 1419,
1373, 1351, 1326, 1246, 1218, 1162, 1073, 1038 cm−1; HRMS (EI)
m/z calcd for [M]+ C10H11ClO2: 198.0448, found: 198.0432;
Chiralpak IA column and IA guard column, 3% i-PrOH/hexanes,
1.0 mL/min flow, λ = 254 nm, minor-isomer tr = 29.5 min and major-
isomer tr = 44.9 min.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00715.
1
Copies of H and 13C{1H} NMR spectra and HPLC
analysis (PDF)
6838
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Article
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