Catalytic asymmetric 1,2-Addition/Lactonization tandem reactions for the syntheses of chiral 3-Substituted phthalides using organozinc reagents

Article abstract of DOI:10.1002/aoc.4643

Using chiral phosphoramide ligand 2d-Zn (II) complex derived from (1R,2R)-1,2-diphenylethylenediamine as the catalyst, we have developed efficient catalytic asymmetric 1,2-addition/lactonization tandem reactions of diverse organozinc reagents with varied methyl 2-formylbenzoates for the construction of optically enriched 3-aryl or alkyl substituted phthalides, which are significant building blocks of many important chiral pharmaceuticals and natural products. The corresponding products could be afforded with good to excellent yields (up to 95%) and moderate to good enantioselectivities (up to 89%).

Full text of DOI:10.1002/aoc.4643

Received: 26 June 2018
DOI: 10.1002/aoc.4643
Revised: 13 September 2018
Accepted: 18 September 2018
F U L L P A P E R
Catalytic asymmetric 1,2‐Addition/Lactonization tandem
reactions for the syntheses of chiral 3‐Substituted
phthalides using organozinc reagents
Huayin Huang
| Yabai Wang | Hua Zong | Ling Song
The Key Laboratory of Coal to Ethylene
Glycol and Its Related Technology, Fujian
Institute of Research on the Structure of
Matter, Chinese Academy of Sciences,
Fuzhou, Fujian 350002, China
Using chiral phosphoramide ligand 2d‐Zn (II) complex derived from (1R,2R)‐
1,2‐diphenylethylenediamine as the catalyst, we have developed efficient cata-
lytic asymmetric 1,2‐addition/lactonization tandem reactions of diverse
organozinc reagents with varied methyl 2‐formylbenzoates for the construction
of optically enriched 3‐aryl or alkyl substituted phthalides, which are signifi-
cant building blocks of many important chiral pharmaceuticals and natural
products. The corresponding products could be afforded with good to excellent
yields (up to 95%) and moderate to good enantioselectivities (up to 89%).
Correspondence
Huayin Huang and Ling Song, The Key
Laboratory of Coal to Ethylene Glycol and
Its Related Technology, Fujian Institute of
Research on the Structure of Matter,
Chinese Academy of Sciences, Fuzhou,
Fujian 350002, China.
KEYWORDS
Email: 409449063@qq.com;
addition,catalysis, lactonization, phthalide, tandem reaction
songling@fjirsm.ac.cn
Funding information
Nature Science Foundation of Fujian
Province, China, Grant/Award Number:
2016J01086; The Strategic Priority
Research Program of the Chinese Acad-
emy of Sciences, Grant/Award Number:
XDB20000000; Chinese Academic of Sci-
ences; Fujian Institute of Research on the
Structure of Matter; The Key Laboratory
of Coal to Ethylene Glycol and Its Related
Technology; Priority Research Program of
the Chinese Academy of Sciences
1 | INTRODUCTION
leukemia (HL‐60).[5] Alcyopterosin E (Figure 1, IV) pos-
sesses cytotoxic activity.[6] Hence, developing efficient
Chiral 3‐substituted phthalides (1(3H)‐isobenzofuranone)
are significant backbones of many biologically natural
products and medications.[1] For example, (S)‐3‐
butylphthalide (Figure 1, I) is a very useful natural prod-
uct with wonderful curative effect for the treatment of
stroke.[2] In addition, it shows anticonvulsant action,
cerebral anti‐ischemic action and so on.[3] Penicidone A
(Figure 1, II) was found to exhibit moderate cytotoxicity
synthetic methodology for the synthesis of optically chiral
3‐substituted phthalides is of great significance.
Despite that a variety of synthetic approaches to 3‐
substituted phthalides have been developed in the past
decades,[1,7,8] asymmetric synthetic approaches to them
are limit.[1] Among these reported asymmetric synthetic
methodologies, chiral auxiliaries were used in most
cases[9] and only a handful of examples using catalytic
asymmetric methods were disclosed.[1,10–20] In 1990,
Noyori and coworkers reported their pioneer work on
preparing chiral 3‐substituted phthalides via catalytic
against
some
tumor
cell
lines.[4]
(+)‐3‐(4′‐
Methoxybenzyl)‐5,7‐dimethoxyphthalide (Figure 1, III)
exhibits cytotoxic activity against human promyelocytic
Appl Organometal Chem. 2018;e4643.
wileyonlinelibrary.com/journal/aoc
© 2018 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4643

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HUANG ET AL.
FIGURE 1 Structures of selected chiral
3‐substituted phthalides
asymmetric hydrogenation/lactonization tandem reac-
tions.[11] Lin group[12] also reported chiral Rh (II)
complexes as catalysts in a tandem process obtaining excel-
lent yields and enantioselectivities. In addition, (S,S)‐
dipamp/Co (II) catalyzed cyclization,[13] Rh(I)‐catalyzed
one‐pot transesterification and [2 + 2 + 2] cycloaddi-
tion,[14] and ProPhenol‐catalyzed asymmetric alkynylation
followed by a Pd‐catalyzed spiroketalization[15] for the syn-
theses of chiral 3‐substituted phthalides were developed.
Moreover, Kitayama and coworkers reported enzymatic
catalytic asymmetric oxidation/lactonization tandem
reactions of ortho‐alkyl benzoate for the syntheses of chiral
3‐substituted phthalides.[16] The enantioselectivity of the
corresponding products could be up to 99%, but the yields
were not satisfied. Furthermore, Wang and coworkers
developed an excellent example of organocatalytic asym-
metric aldol/lactonization reaction of 2‐formylbenzoic
esters with ketones/aldehydes for constructing
enantioenriched 3‐substituted phthalides.[17]
Besides the above mentioned approaches, catalytic
asymmetric 1,2‐addition/lactonization tandem reactions
using diorganozinc reagent with methyl 2‐formylbenzoate
is a promising transformation.[18,19] In 2014, Chang and
coworkers reported an excellent method on chiral amino
alcohol ligand catalyzed one‐pot arylation/lactonization
tandem reactions of 2‐formylbenzoate with in situ
generated arylzinc reagent. The corresponding 3‐aryl
substituted chiral phthalides could be obtained with
excellent yields and enantioselectivities.[19] Despite that
pioneering studies have been reported on the catalytic
asymmetric preparation of 3‐substituted chiral phthalides,
the development of highly efficient asymmetric catalytic
systems with wide substrate scope using readily prepared
chiral ligand is still highly desirable.
of diorganozinc reagents with methyl 2‐formylbenzoates
for the construction of 3‐substituted chiral phthalides.
2 | RESULTS AND DISCUSSION
Initially, we used a reaction of catalytic asymmetric 1,2‐
addition/lactonization of methyl 2‐formylbenzoate
with in situ generated arylzinc reagent using Zn‐B
exchange method[25] to screen phosphoramide chiral
ligands. The results are listed in Table 1. When 10 mol%
(1R,2R)‐1,2‐diaminocyclohexane derived phosphoramide
ligand 1 was used, the desired product of chiral 3‐aryl
substituted phthalide 3a was afforded with 88% yield
and 11% ee (Table 1, Entry 1). The reaction with the use
of chiral (1R,2R)‐1,2‐diphenylethylenediamine derived
phosphoramide ligand 2a proceeded to give 3a with 81%
yield and 31% ee (Table 1, Entry 2). Chiral (1R,2R)‐1,2‐
diphenylethylenediamine derived N,N‐disubstituted
phosphoramide 2b gave the chiral product 3a with high
yield but only 17% ee (Table 1, Entry 3). When N‐methyl,
N‐isopropyl disubstituted phosphoramide 2c was used,
the product 3a was afforded with 89% yield and 63% ee
(Table 1, Entry 4). Then, a series of N‐mono substituted
phosphoramide chiral ligands were evaluated (Table 1,
Entries 5–8). Chiral phosphoramide 2d was found
to be the best chiral ligand of choice affording the
corresponding product 3a with 92% yield and 77% ee
(Table 1, Entry 5).
Next, the reaction conditions, such as solvent, reac-
tion temperature and the loading amount of chiral ligand
were optimized. The results are listed in Table 2. Differ-
ent solvents such as toluene, hexane, NMP and THF were
examined and the mixed solvent (toluene/hexane = 1:2)
was found to be the best solvent. The resulting product
3a was afforded with 92% yield and 77% ee (Table 2,
Entries 1–5). The effect of temperature was studied
subsequently. The yield and ee increased a little when
the reaction temperature was decreased (Table 2, Entries
6). When further decreasing the temperature to −40 °C,
chiral product 3a was obtained with 90% yield and 79% ee
(Table 2, Entry 7). Increasing the loading amount of
chiral ligand to 20 mol%, good enantioselectivity of the
product was obtained (82% ee, Table 2, Entry 8). When
30 mol% of chiral ligand 2d was used, 91% yield and
Chiral 1,2‐diamino phosphoramide ligands are very
efficient in the organozinc participated catalytic asym-
metric reactions,[20–22] organocatalyzed asymmetric reac-
tions[23] and enantiodiscrimination of chiral acids.[24] In
our previous study, chiral 1,2‐diamino phosphoramide‐
Zn (II) complex exhibited excellent effect in the aryl
transform addition reactions of aldehydes with in situ
generated arylalkylzinc reagents.21j As an effort to explore
the application of phosphoramide‐Zn (II) catalyzed asym-
metric reactions, we herein report an example of catalytic
asymmetric 1,2‐addition/lactonization tandem reactions

HUANG ET AL.
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TABLE 1 Screening of chiral 1,2‐diamino phosphoramide ligands in the catalytic asymmetric 1,2‐addition/lactonization tandem reaction
of methyl 2‐formylbenzoate with in situ generated arylzinc reagenta
Entry
Ligand
NR1R2
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1
N (CH2)5
N (CH2)5
NEt2
88
81
85
89
92
90
91
90
11
31
17
63
77
70
75
69
2a
2b
2c
2d
2e
2f
NMei‐Pr
NHi‐Pr
NHCH2Bu
NHCy
2 g
NHCH2Ph
aUnless otherwise noted, all reactions were carried out with methyl 2‐formylbenzoate in 0.5 mmol scale.
bIsolated yields.
cDetermined by chiral GC analysis. The absolute configuration was assigned by comparison of the sign of specific rotation value with the literature (Lit.8h [α]
D
28
= −39.6 (c 1.0, CHCl3) for 90% ee (R)).
TABLE 2 Optimization of reaction conditions for the catalytic asymmetric 1,2‐addition/lactonization tandem reaction of methyl 2‐
formylbenzoatea
Entry
x (mol%)
Temp.
Time
Solvent
Yieldb (%)
eec (%)
1d
2
10
10
10
10
10
10
10
20
30
0 °C
12 h
12 h
12 h
12 h
12 h
24 h
24 h
24 h
24 h
Toluene/hexane
Toluene
92
77
0 °C
90
75
3
0 °C
Hexane
89
74
4
0 °C
Hexane/NMP
Hexane/THF
Toluene/hexane
Toluene/hexane
Toluene/hexane
Toluene/hexane
trace
trace
92
N.D.d
N.D.d
78
5
0 °C
6
−20 °C
−40 °C
−40 °C
−40 °C
7
90
79
8e
90
82
9
91
82
aUnless otherwise noted, all reactions were carried out with methyl 2‐formylbenzoate in 0.5 mmol scale.
bIsolated yields.
cDetermined by chiral GC analysis. The absolute configuration was assigned by comparison of the sign of specific rotation value with the literature (Lit.8h [α]
D
28
= −39.6 (c 1.0, CHCl3) for 90% ee (R)).
dNot determined.
eThe recovery of 2d was 95%.

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HUANG ET AL.
TABLE 3 Catalytic enantioselective 1,2‐addition/lactonization tandem reactions of methyl 2‐formylbenzoates using 2d as the chiral liganda
Entry
Product
Name
Yieldb(%)
eec (%)
1
(R)‐3a
91
82
2
3
4
(R)‐3b
(R)‐3c
(R)‐3d
85
95
83
76
74
73
5
6
(R)‐3e
(R)‐3f
81
82
87
78
7
8
(R)‐3 g
(R)‐3 h
85
84
84
76
9
(R)‐3i
80
83
(Continues)

HUANG ET AL.
5 of 12
82% ee of the product was observed (Table 2, Entry 9).
Thus, the reaction was best performed using 2 equiva-
lents of phenyl boronic acid and 10 equivalents of Et2Zn
with 20 mol% chiral ligand 2d in mixed solvent (tolu-
ene/hexane = 1:2) at −40 °C for 24 hr. Despite that rela-
tively high loading amount of chiral ligand 2d (20 mol%)
was required to achieve high level of enantioselectivity, it
could be easily recovered by flash column chromatogra-
phy from the reaction mixture after usual workup.
With the optimized conditions in hand, we investigated
the substrate scope and limitation of the catalytic asym-
metric tandem reaction system with the use of (1R,2R)‐
TABLE 3 (Continued)
Entry
Product
Name
Yieldb(%)
eec (%)
10
11
(R)‐3j
86
82
71
72
(R)‐3 k
12
13
14
(R)‐3 l
(R)‐3 m
(R)‐3n
86
83
86
73
62
81
aUnless otherwise noted, all reactions were carried out with methyl 2‐formylbenzoate in 0.5 mmol scale.
bIsolated yields.
cDetermined by chiral GC or HPLC analysis.

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HUANG ET AL.
TABLE 4 Catalytic enantioselective 1, 2‐addition/lactonization tandem reactions of methyl 2‐formylbenzoates with dialkylzinc reagent
using 2d as the chiral liganda
Entry
Product
Name
Yieldb(%)
eec (%)
1
(R)‐3o
92 (90)d (86)e
89 (86)d (87)e
2
3
4
(R)‐3p
(R)‐3q
(R)‐3r
87
82
83
82
83
81
aUnless otherwise noted, all reactions were carried out with methyl 2‐formylbenzoate in 0.5 mmol scale.
bIsolated yields.
cDetermined by chiral GC or HPLC analysis.
d10 mol% chiral ligand 2d was used and the reaction temperature was −20 °C.
e1.64 g (10 mmol) of methyl 2‐formylbenzoate was used as substrate.
1,2‐diphenylethylenediamine derived phosphoramide
ligand 2d. As shown in Table 3, using phorsporamide 2d
as the chiral ligand, the catalytic asymmetric 1,2‐addi-
tion/lactonization tandem reaction of methyl 2‐
formylbenzoate with a variety of arylzinc reagents in situ
generated from aromatic boric acids took place, affording
the anticipated chiral 3‐aryl substituted phthalides in good
to excellent yields (80–95% yields) and with good
enantioselectivities (73–87% ee) (Table 3, Entries 1–9).
Aromatic boric acids with electron‐withdrawing or
electro‐donating substituents at the ortho‐, meta‐, and
para‐positions of the benzene rings worked well. When
1‐naphthylboronic acid and 2‐naphthylboronic acid were
used as aryl transferring resources, the corresponding
products were obtained with moderate yields and
enantioselectivities (Table 3, Entries 10 and 11). Some
substituted methyl 2‐formylbenzoates were examined,
and the corresponding products 3 l‐n were all obtained
in good yields with moderate to good ee values
(Table 3, Entries 12–14). We further tried to use methyl
2‐acetylbenzoate as the substrate to react with in situ
generated ArZnEt species for the construction of oxygen‐
containing tetrasubstituted stereogenic center, but no
product was observed under the optimized reaction condi-
tions owning to the relatively lower activity of the carbonyl
group of ketone than that of aldehyde.[26]
Finally, we tried to use chiral ligand 2d in the cata-
lytic enantioselective 1,2‐addition/lactonization tandem
reactions of methyl 2‐formylbenzoates with diethylzinc
reagent for the synthesis of 3‐alkylated chiral phthalide.
As shown in Table 4, chiral 3‐alkylated phthalide could
be afforded with excellent yields (up to 92%) and
enantioselectivities (up to 89%). Particularly, a 1‐g‐scale
(10 mmol) preparation of (R)‐3o was established, the cor-
responding product was obtained in 86% yield with 87%
ee under optimized reaction conditions (Table 4, Entry 1).
FIGURE 2 Proposed mechanism for
transition zinc‐catalyzed asymmetric 1,2‐
addition/lactone reactions of organozinc
reagents with 2‐formylbenzoates to access
3‐substituted phthalides

HUANG ET AL.
7 of 12
In the end, the mechanism was proposed.10j, 17, 19 As
at 0 °C. The solution was stirred for 30 min at room tem-
perature, and then heated at 60 °C for 12 hr. Under N2
atmosphere, to a solution of chrial ligand 2d (0.2 equiv.)
in toluene (0.5 mL), the above in situ generated arylzinc
solution was added at 0 °C and stirred for 30 min, then
the reaction mixture was cooled to −40 °C and methyl
2‐formylbenzoate (0.5 mmol) was then added immedi-
ately at −40 °C. The mixture was stirred for 24 hr and
quenched by adding aqueous HCl (1.0 M, 5 ml). Extrac-
tion with EtOAc (10 ml × 3) gave combined organic
layers that were washed with brine (10 ml), dried
over anhydrous Na2SO4 and concentrated in vacuo to
give a residue which was subjected to silica gel column
chromatography (EtOAc/hexane = 1/20), affording the
corresponding enantio‐enriched 3‐substituted phthalide
3. The ee value was determined by Chiral GC or
HPLC. The absolute configuration of the phthalide was
assigned as (R) by comparison of the optical rotation with
reported data.
shown in Figure 2, the active arylethylzinc specie was in
situ generated by boron to zinc transmetalation. Then it
reacted with 2‐formylbenzoate to form the diarylmethoxy
alkyl zinc intermediate 4 which further generated 3‐
substituted phthalides 3 via lactone formation.
3 | CONCLUSIONS
In summary, an efficient catalytic asymmetric 1,2‐addi-
tion/lactonization tandem reaction of organozinc
reagents with methyl 2‐formylbenzoates using
phosphoramide ligand 2d‐Zn (II) complex as the catalyst
was developed. This method provides a direct and conve-
nient way to prepare functionalized 3‐aryl or alkyl
substituted chiral phthalides with moderate to good
enantioselectivities (up to 89%) from readily commercial
available arylboronic acids, diorganozinc reagents and
methyl 2‐formylbenzoates.
4 | EXPERIMENTAL SECTION
4.1 | General Methods
4.2.1 | 3‐Phenylisobenzofuran‐1(3H)‐one
(3a)8h
White solid, mp 118–119 °C; 91% yield, 82% ee. The ee
value was determined by Chiral GC Chirasil Dex CB
[Column temperature: 165 °C, tR = 30.88 min (S),
tR = 31.72 min (R)], retention time: 30.88 min (minor)
and 31.72 min (major)), tR = 30.88 min (S), tR = 31.72 min
(R)]; [α]D31.8 = −15.7 (c 0.5, CHCl3) (Lit.8h [α]D28 = −39.6
(c 1.0, CHCl3) for 90% ee (R)); 1H NMR (400 MHz, CDCl3)
δ 7.97 (d, J = 7.6 Hz, 1H), 7.65–7.72 (m, 1H), 7.55–7.63
(m, 1H), 7.39–7.43 (m, 3H), 7.33–7.38 (m, 1H), 7.26–7.30
(m, 2H), 6.41 (s, 1H); 13C NMR (101 MHz, CDCl3) δ
170.59, 149.72, 136.43, 134.40, 129.37, 129.01, 127.00,
125.60, 122.93, 82.76.
All experiments were carried out in dried glassware with
magnetic stirring under an atmosphere of dry nitrogen.
1H NMR (400 MHz), 13C NMR (100 MHz) and 19F NMR
(376 MHz) spectra were recorded in CDCl3 solutions
using a 400 MHz spectrometer. Chemical shifts were
reported in parts per million (ppm, δ) relative to CDCl3
(δ 7.26 for 1H NMR), or CDCl3 (δ 77.0 for 13C NMR). Mul-
tiplicities are indicated as s (singlet), d (doublet), t (trip-
let), q (quartet), m (multiplet). Commercial reagents
were used as received unless otherwise indicated. All sol-
vents were purified and dried prior to use according to
standard methods.[27] Optical rotations were measured
T
on a polarimeter and reported as follows: [α]D (c g/
100 mL, solvent). The high performance liquid chroma-
tography (HPLC) analysis was performed using Chiralcel
AD‐H or OD‐H column. GC analysis was performed on a
gas chromatograph with a FID detector on fused silica
chiral capillary column (Chirasil Dex CB column, 25 m
Length × 0.32 mm ID × 0.25 mm film thickness). Chiral
ligands 1,21a 2a,21e 2b,21e 2c,21e 2d,21e 2e,21e 2f21e and
2 g21e were synthesized according to reported methods.
4.2.2 | 3‐(o‐Tolyl)isobenzofuran‐1(3H)‐one
(3b)10k
White solid, mp 108–109 °C; 85% yield, 76% ee. The ee
value was determined by Chiral HPLC analysis with a
Chiralcel AD‐H column [(10% IPA/hexane, 1.0 ml/min,
220 nm, retention time: 8.96 min (major) and 9.65 min
(minor)), tR = 8.96 min (R), tR = 9.65 min (S)]; [α]
= +17.1 (c 1.0, CHCl3) (Lit.10k [α]D = +41.6 (c
31.6
D
22
1
0.62, CHCl3) for 82% ee (R)); H NMR (400 MHz, CDCl3)
δ 7.99 (d, J = 7.6 Hz, 1H), 7.42–7.78 (m, 3H), 7.22–7.41
(m, 2H), 7.09–7.20 (m, 1H), 6.93 (d, J = 7.6 Hz, 1H),
6.70 (s, 1H), 2.52 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.65, 149.30, 137.18, 134.21, 134.10, 131.14, 129.38,
129.33, 127.28, 126.43, 125.76, 123.04, 80.55, 19.35.
4.2 | General Procedure For Catalytic
Asymmetric Synthesis Of Chiral Phthalide
Under N2 atmosphere, to a reaction tube which contained
corresponding arylboronic acid (1.0 mmol) and toluene
(2 ml) was added diethylzinc (5.0 ml, 1.0 M in hexane)

8 of 12
HUANG ET AL.
Chiralcel AD‐H column [(10% IPA/hexane, 1.0 ml/min,
220 nm, retention time: 11.98 min (major) and
4.2.3 | 3‐(m‐Tolyl)isobenzofuran‐1(3H)‐
one (3c)10k
14.82 min (minor)), tR = 11.98 min (R), tR = 14.82 min
White solid, mp 85–86 °C; 95% yield, 74% ee. The ee value
was determined by Chiral HPLC analysis with a Chiralcel
AD‐H column [(10% IPA/hexane, 1.0 ml/min, 220 nm,
retention time: 8.63 min (major) and 10.93 min (minor)),
tR = 8.63 min (R), tR = 10.93 min (S)]; [α]D30.8 = −10.2 (c
31.1
(S)]; [α]D
= −13.5 (c 1.0, CHCl3) (Lit.10k [α]
22
1
= −32.2 (c 0.72, CHCl3) for 88% ee (R)); H NMR
D
(400 MHz, CDCl3) δ 7.99 (d, J = 7.6 Hz, 1H), 7.66–7.76
(m, 1H), 7.56–7.63 (m, 1H), 7.31–7.42 (m, 3H), 7.20–7.28
(m, 2H), 6.40 (s, 1H); 13C NMR (101 MHz, CDCl3) δ
170.25, 149.24, 135.33, 134.98, 134.50, 129.61, 129.26,
128.39, 125.82, 125.53, 122.78, 81.86.
1.0, CHCl3) (Lit.10k [α]D = −40.5 (c 1.18, CHCl3) for
22
90% ee (R)); 1H NMR (400 MHz, CDCl3) δ 7.99 (d,
J = 7.6 Hz, 1H), 7.63–7.73 (m, 1H), 7.51–7.62 (m, 1H),
7.34–7.39 (m, 1H), 7.26–7.33 (m, 1H), 7.17–7.24 (m, 1H),
7.06–7.15 (m, 2H), 6.40 (s, 1H), 2.36 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 170.65, 149.83, 138.85, 136.34,
134.34, 130.08, 129.33, 128.86, 127.49, 125.61, 125.55,
124.08, 122.90, 82.84, 21.38.
4.2.7 | 3‐(3‐Methoxyphenyl)
isobenzofuran‐1(3H)‐one (3 g)10k
White solid, mp 78–80 °C; 85% yield, 84% ee. The ee value
was determined by Chiral HPLC analysis with a Chiralcel
AD‐H column [(10% IPA/hexane, 1.0 ml/min, 220 nm,
retention time: 12.74 min (major) and 17.89 min
(minor)), tR = 12.74 min (R), tR = 17.89 min (S)]; [α]
4.2.4 | 3‐(p‐Tolyl)isobenzofuran‐1(3H)‐one
(3d)10k
= −16.5 (c 1.0, CHCl3) (Lit.10k [α]D = −30.4 (c
31.6
D
22
1
Light yellow solid, mp 121–122 °C; 83% yield, 73% ee. The
ee value was determined by Chiral HPLC analysis with a
Chiralcel AD‐H column [(10% IPA/hexane, 1.0 ml/min,
220 nm, retention time: 10.47 min (major) and 15.70 min
(minor)), tR = 10.47 min (R), tR = 15.70 min (S)]; [α]
0.68, CHCl3) for 87% ee (R)); H NMR (400 MHz, CDCl3)
δ 7.98 (d, J = 7.6 Hz, 1H), 7.56–7.78 (m, 2H), 7.23–7.49
(m, 2H), 6.75–7.04 (m, 3H), 6.39 (s, 1H), 3.79 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 170.56, 160.01, 149.62,
137.93, 134.37, 130.09, 129.41, 125.68, 125.47, 122.86,
119.12, 114.65, 112.41, 82.55, 55.34.
30.9 = −6.3 (c 1.0, CHCl3) (Lit.10k [α]D22 = −15.2 (c 0.78,
D
CHCl3) for 92% ee (R)); 1H NMR (400 MHz, CDCl3) δ 7.97
(d, J = 7.5 Hz, 1H), 7.51–7.75 (m, 2H), 7.34 (d, J = 7.6 Hz,
1H), 7.09–7.25 (m, 4H), 6.40 (s, 1H), 2.37 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 170.63, 149.84, 139.36, 134.31,
133.98, 133.40, 129.66, 129.31, 129.08, 127.08, 125.71,
125.69, 125.59, 122.90, 121.77, 82.80, 21.26.
4.2.8 | 3‐(4‐Methoxyphenyl)
isobenzofuran‐1(3H)‐one (3 h)10k
White solid, mp 126–127 °C; 84% yield, 76% ee. The ee
value was determined by Chiral HPLC analysis with a
Chiralcel AD‐H column [(10% IPA/hexane, 1.0 ml/min,
220 nm, retention time: 16.13 min (major) and
4.2.5 | 3‐(3‐Chlorophenyl)isobenzofuran‐
1(3H)‐one (3e)[19]
21.43 min (minor)), tR = 16.13 min (R), tR = 21.43 min
31.3
(S)]; [α]D
= +21.3 (c 0.5, CHCl3) (Lit.10k [α]
= +31 (c 0.42, CHCl3) for 98% ee (R)); 1H NMR
22
White solid, mp 116–117 °C; 81% yield, 87% ee. The ee
value was determined by Chiral HPLC analysis with a
Chiralcel AD‐H column [(10% IPA/hexane, 1.0 ml/min,
220 nm, retention time: 10.34 min (major) and
D
(400 MHz, CDCl3) δ 7.99 (d, J = 7.6 Hz, 1H), 7.53–7.80
(m, 2H), 7.13–7.40 (m, 3H), 6.85–6.96 (m, 2H), 6.40 (s,
1H), 3.82 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.56,
160.42, 149.77, 134.27, 129.32, 128.82, 128.29, 125.59,
122.96, 114.34, 82.76, 55.37.
12.76 min (minor)), tR = 10.34 min (R), tR = 12.76 min
31.4
(S)]; [α]D
=
−19.7 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 1H), 7.53–7.79
(m, 2H), 7.02–7.47 (m, 5H), 6.38 (s, 1H); 13C NMR
(101 MHz, CDCl3) δ 170.23, 149.06, 138.49, 134.93,
134.60, 130.36, 129.68, 129.49, 126.95, 125.82, 125.35,
125.10, 122.83, 81.70.
4.2.9 | 3‐(4‐(Trifluoromethyl)phenyl)
isobenzofuran‐1(3H)‐one (3i)[15]
Light yellow solid, mp 101–102 °C; 80% yield, 83% ee. The
ee value was determined by Chiral HPLC analysis with a
Chiralcel AD‐H column [(10% IPA/hexane, 1.0 ml/min,
220 nm, retention time: 9.98 min (major) and 11.10 min
(minor)), tR = 9.98 min (R), tR = 11.10 min (S)]; [α]
4.2.6 | 3‐(4‐Chlorophenyl)isobenzofuran‐
1(3H)‐one (3f)10k
31.4
D
1
White solid, mp 120–122 °C; 82% yield, 78% ee. The ee
value was determined by Chiral HPLC analysis with a
= −19.8 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3)
δ 8.01 (d, J = 7.6 Hz, 1H), 7.56–7.77 (m, 4H), 7.46 (d,

HUANG ET AL.
9 of 12
J = 8.0 Hz, 2H), 7.76 (d, J = 7.6 Hz, 1H), 6.48 (s, 1H); 13
C
4.2.13 | 3‐(4‐Tert‐butylphenyl)‐6‐
NMR (101 MHz, CDCl3) δ 170.17, 148.97, 140.48, 134.62,
131.62, 131.30, 129.77, 127.11, 126.07, 126.35, 125.98,
125.30, 122.69, 122.40, 81.58; 19F NMR (376 MHz, CDCl3)
δ −62.77 (s).
fluoroisobenzofuran‐1(3H)‐one (3 m)
White solid, mp 70–72 °C; 83% yield, 62% ee. The ee value
was determined by Chiral HPLC analysis with a Chiralcel
OD‐H column [(6% IPA/hexane, 1.0 ml/min, 220 nm,
retention time: 8.00 min (minor) and 8.59 min (major)),
24.5
tR = 8.00 min (S), tR = 8.59 min (R)]; [α]D
= −2.3 (c
4.2.10 | 3‐(Naphthalen‐1‐yl)isobenzofuran‐
1(3H)‐one (3j)9c
1
1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 7.54–7.66 (m,
1H), 7.30–7.50 (m, 4H), 7.13–7.25 (m, 2H), 6.40 (s, 1H),
1.33 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 169.4 (d,
J = 3.7 Hz), 164.5, 162.0, 152.7, 145.3 (d, J = 2.2 Hz),
132.9, 127.9, 127.8, 126.4 (d, J = 84.3 Hz), 124.8 (d,
J = 8.6 Hz), 122.3 (d, J = 23.9 Hz), 118.8 (d, J = 23.6 Hz),
82.6, 34.7, 31.2; 19F NMR (376 MHz, CDCl3) δ −111.2 (m).
Light yellow solid, mp 174–176 °C; 86% yield, 71% ee. The
ee value was determined by Chiral HPLC analysis with a
Chiralcel AD‐H column [(10% IPA/hexane, 1.0 ml/min,
220 nm, retention time: 12.71 min (major) and
13.92 min (minor)), tR = 12.71 min (R), tR = 13.92 min
30.7
(S)]; [α]D
=
−34.3 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 8.02 (d, J = 7.6 Hz, 1H), 7.80–7.98
(m, 4H), 7.50–7.77 (m, 4H), 7.36 (d, J = 7.6 Hz, 1H),
7.22–7.30 (m, 1H), 6.58 (s, 1H); 13C NMR (101 MHz,
CDCl3) δ 170.67, 149.75, 134.45, 133.71, 133.61, 133.09,
129.49, 129.19, 128.13, 127.84, 126.87, 126.74, 125.74,
125.63, 123.81, 122.97, 83.00.
4.2.14 | 3‐(4‐Fluorophenyl)‐5,6‐
dimethoxyisobenzofuran‐1(3H)‐one (3n)
White solid, mp 132–134 °C; 86% yield, 81% ee. The ee
value was determined by Chiral HPLC analysis with a
Chiralcel AD‐H column [(10% IPA/hexane, 1.0 ml/min,
220 nm, retention time: 20.78 min (minor) and
21.85 min (major)), tR = 20.78 min (S), tR = 21.85 min
=
+16.9 (c 1.0, CHCl3); 1H NMR
22.0
(R)]; [α]D
4.2.11 | 3‐(Naphthalen‐2‐yl)isobenzofuran‐
1(3H)‐one (3 k)10j
(400 MHz, CDCl3) δ 7.20–7.39 (m, 3H), 6.98–7.15 (m,
2H), 6.67 (s, 1H), 6.27 (s, 1H), 3.96 (s, 3H), 3.89 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 170.6, 164.4, 161.9, 132.5
(d, J = 3.2 Hz), 129.2 (d, J = 8.6 Hz), 117.6, 116.0 (d,
J = 21.9 Hz), 104.9 (d, J = 187.6 Hz), 81.5, 56.43, 56.35;
19F NMR (376 MHz, CDCl3) δ −111.8 (m).
White solid, mp 156–157 °C; 82% yield, 72% ee. The ee
value was determined by Chiral HPLC analysis with a
Chiralcel AD‐H column [(10% IPA/hexane, 1.0 ml/min,
220 nm, retention time: 14.59 min (major) and
16.42 min (minor)), tR = 14.59 min (R), tR = 16.42 min
31.8
1
(S)]; [α]D
= −6.3 (c 1.0, CHCl3); H NMR (400 MHz,
CDCl3) δ 8.03 (d, J = 7.6 Hz, 1H), 7.82–7.95 (m, 4H),
7.50–7.71 (m, 4H), 7.37 (d, J = 7.6 Hz, 1H), 7.21–7.31
(m, 1H), 6.59 (s, 1H); 13C NMR (101 MHz, CDCl3) δ
170.64, 149.75, 134.42, 133.69, 133.61, 133.10, 129.48,
129.12, 128.11, 127.84, 126.86, 126.74, 125.75, 125.65,
123.81, 122.96, 82.96, 77.37, 77.06, 76.74.
4.2.15 | 3‐Ethylisobenzofuran‐1(3H)‐one
(3o)[12]
Colorless oil; 92% yield, 89% ee. The ee value was deter-
mined by Chirasil Dex CB [Column temperature:
130 °C, tR = 17.03 min (R), tR = 17.77 min (S)], retention
time: 17.00 min (major) and 17.77 min (minor)),
22.1
tR = 17.00 min (R), tR = 17.77 min (S)]; [α]D
= +38.4
(c 1.0, CHCl3) (Lit.[12] [α]D = −76 (c 0.95, CHCl3) for
97.7% ee (S)); 1H NMR (400 MHz, CDCl3) δ 7.85 (d,
J = 7.6 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.37–7.58 (m,
2H), 5.35–5.49 (m, 1H), 1.99–2.20 (m, 1H), 1.69–1.87 (m,
1H), 0.96 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ 170.76, 149.73, 134.02, 129.04, 126.19, 125.54, 121.81,
82.35, 27.59, 8.78.
26
4.2.12 | 3‐(4‐Tert‐butylphenyl)‐6‐
bromoisobenzofuran‐1(3H)‐one (3 l)
White solid, mp 101–102 °C; 86% yield, 73% ee. The ee value
was determined by Chiral HPLC analysis with a Chiralcel
OD‐H column [(6% IPA/hexane, 1.0 ml/min, 220 nm,
retention time: 8.31 min (minor) and 9.08 min (major)),
22.6
tR = 8.31 min (S), tR = 9.08 min (R)]; [α]D
= −4.4 (c
1
1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 8.03–8.17 (m,
1H), 7.72–7.82 (m, 1H), 7.36–7.48 (m, 2H), 7.13–7.33 (m,
3H), 6.38 (s, 1H), 1.32 (s, 9H); 13C NMR (101 MHz, CDCl3)
δ 168.9, 152.8, 148.4, 137.3, 132.6, 128.6, 127.9, 126.9, 126.1,
124.6, 123.3, 82.7, 34.7, 31.2.
4.2.16 | 6‐Bromo‐3‐ethylisobenzofuran‐
1(3H)‐one (3p)[28]
White solid, mp 53–55 °C; 87% yield, 82% ee. The ee value
was determined by Chirasil Dex CB [Column temperature:

10 of 12
HUANG ET AL.
150 °C, tR = 23.32 min (R), tR = 24.52 min (S)], retention
ORCID
time: 23.32 min (major) and 24.52 min (minor)),
Huayin Huang http://orcid.org/0000-0002-3923-095X
24.1
tR = 23.32 min (R), tR = 24.52 min (S)]; [α]D
= +25.0
1
(c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 7.95–7.99
(m, 1H), 7.71–7.83 (m, 1H), 7.29–7.43 (m, 1H), 5.35–5.45
(m, 1H), 2.02–2.19 (m, 1H), 1.74–1.90 (m, 1H), 0.97 (t,
J = 7.38 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.0,
148.4, 137.0, 128.6, 128.4, 123.5, 123.0, 82.3, 27.5, 8.8.
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4.2.17 | 3‐Ethyl‐6‐fluoroisobenzofuran‐
1(3H)‐one (3q)
Colorless oil; 82% yield, 83% ee. The ee value was deter-
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130 °C, tR = 15.86 min (R), tR = 16.45 min (S)], retention
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21.3
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1
(c 0.5, CHCl3); H NMR (400 MHz, CDCl3) δ 7.51–7.59
(m, 1H), 7.35–7.47 (m, 2H), 5.41–5.50 (m, 1H), 2.00–2.20
(m, 1H), 1.69–1.95 (m, 1H), 1.00 (t, J = 7.4 Hz, 3H); 13C
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(d, J = 249.1 Hz), 145.2 (d, J = 2.1 Hz), 128.3 (d,
J = 8.9 Hz), 123.4 (d, J = 8.4 Hz), 121.9 (d, J = 8.4 Hz),
112.0 (d, J = 23.6 Hz), 82.2, 27.7, 8.8; 19F NMR
(376 MHz, CDCl3) δ −111.7 (m).
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4.2.18 | Ethyl‐5,6‐
dimethoxyisobenzofuran‐1(3H)‐one (3r)
White solid, mp 100–101 °C; 83% yield, 81% ee. The ee
value was determined by Chiral HPLC analysis with a
Chiralcel OD‐H column [(4% IPA/hexane, 0.8 ml/min,
220 nm, retention time: 26.94 min (minor) and
30.99 min (major)), tR = 26.94 min (S), tR = 30.99 min
23.6
(R)]; [α]D
=
+13.4 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.21–7.30 (m, 1H), 6.83 (s, 1H),
5.29–5.39 (m, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 1.97–2.22
(m, 1H), 1.66–1.86 (m, 1H), 0.98 (t, J = 7.25 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 171.0, 154.7, 150.4, 144.3,
118.2, 106.0, 103.1, 81.7, 56.4, 56.3.
ACKNOWLEDGEMENTS
We gratefully acknowledge financial support from the
Nature Science Foundation of Fujian Province, China
(No. 2016 J01086). We also thank the Strategic Priority
Research Program of the Chinese Academy of Sciences
(No. XDB20000000) and The Key Laboratory of Coal to
Ethylene Glycol and Its Related Technology, Fujian Insti-
tute of Research on the Structure of Matter, Chinese Aca-
demic of Sciences.

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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
How to cite this article: Huang H, Wang Y,
Zong H, Song L. Catalytic asymmetric 1,2‐
Addition/Lactonization tandem reactions for the
syntheses of chiral 3‐Substituted phthalides using
organozinc reagents. Appl Organometal Chem.
2018;e4643. https://doi.org/10.1002/aoc.4643