Titanium Tetrachloride-Mediated Approach to Access 2-Chloro-2-Substituted Isoindolin-1-ones through the Addition of Alkynes to Acyliminium ions

Article abstract of DOI:10.1002/ejoc.202100368

An asymmetric approach to access 2-substituted isoindolin-1-ones 9–11 was developed through TiCl₄-mediated addition-chlorination of N,O-acetals 7 a–7 c with terminal alkynes 8. A range of substrates were amenable to this transformation, and the desired substituted isoindolin-1-ones were obtained in moderate to good yields with moderate diastereoselectivities.

Full text of DOI:10.1002/ejoc.202100368

Full Papers
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Titanium Tetrachloride-Mediated Approach to Access
2-Chloro-2-Substituted Isoindolin-1-ones through the
Addition of Alkynes to Acyliminium ions
Wen-Ke Xu,[a] Jia-Ming Guo,[a] Zhao-Dan Chen,[a] Chang-Mei Si,*[a] and Bang-Guo Wei*[a]
An asymmetric approach to access 2-substituted isoindolin-1-
ones 9–11 was developed through TiCl4-mediated addition-
chlorination of N,O-acetals 7a–7c with terminal alkynes 8. A
range of substrates were amenable to this transformation, and
the desired substituted isoindolin-1-ones were obtained in
moderate to good yields with moderate diastereoselectivities.
Introduction
The enantioselective construction of a stereogenic center at the
�-position of nitrogen-containing heterocycles (N-heterocycles)
is one of the most challenging tasks in synthetic heterocyclic
chemistry.[1] Chiral isoindolinone skeleton (1) (Figure 1), which is
prevalent in many natural products[2] and serves as a sub-
structure for numerous biologically pharmaceutical agents,[3,4]
has attracted significant interest in synthetic and medicinal
chemistry. Typical examples include Lennoxamine (2), which
was isolated from the plants of Chilean Berberis species,[2d] (R)-
JM1232 (3), Pazinaclone (4), Pagoclone (5) and (S)-PD-172938
(6). In particular, (S)-PD 172938 (6) shows potent affinity for
dopamine D4 receptor,[5] and Pazinaclone (4) is currently used as
sedative and anxiolytic drug.[6] Meanwhile, tremendous efforts
have been devoted to the construction of a chiral functionalized
isoindolinone scaffold (1) and several asymmetric syntheses
have been reported.[7]
Figure 1. Structures of several natural products.
Two general approaches were applied to construct such a
chiral functionalized isoindolinone scaffold. One approach was
to use powerful catalytic enantioselective syntheses including
Mannich-lactamization,[8] aza-Michael addition,[9] enantioselec-
tive aza-Wacker-type cyclization,[10] and tandem Mannich-
lactamization.[11] The other approach was to use a chiral
auxiliary group in the reaction substrates. For examples, Allin et
al established a new approach to the synthesis of 2-allyl
substituted isoindolin-1-one through the application of a cyclic
N,O-acetal chiral substrate as a N-acylhninium ion precursor in
1999 (Figure 2a).[12] Huang et al established a diastereoselective
approach to chiral substituted isoindolinones through the
successive addition-reduction process from chiral 2-(2-hydroxy-
1-phenylethyl)isoindoline-1,3-dione in 2005 (Figure 2b).[13] In
2019, Allin’s group used the cyclic N,O-acetal chiral substrate to
Figure 2. The asymmetric methods based on chiral substrates.
[a] W.-K. Xu, J.-M. Guo, Z.-D. Chen, Dr. C.-M. Si, Prof. Dr. B.-G. Wei
Department of Natural Medicine,School of Pharmacy
Fudan University
826 Zhangheng Road, Shanghai 201203, China
E-mail: bgwei1974@fudan.edu.cn
synthesize 2-alkyl/aryl substituted- isoindolin-1-ones (Fig-
ure 2c).[14]
sicm@fudan.edu.cn
N-Acyliminium ions, acting as important organic synthetic
intermediates, are widely used in the formation of CÀ C and
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100368
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CÀ heteroatom bonds,[15] mostly through intermolecular
method,[13,20] with phenylacetylene. The reaction could not take
place in the absence of Lewis acid (Table 1, entry 1). When
TMSOTf was examined, the reaction was complicated (Table 1,
entry 2). When AuCl3, TMSCl, ZnCl2 and AlCl3 were examined, no
product was observed (Table 1, entries 3–6). SnCl4 could afford
the desired product 9a in 62% yield, albeit with low
diastereoselectivity (dr=62:38, Table 1, entry 7). When TiCl4
was examined, the desired product 9a was isolated in 68%
yield with 85:15 diastereoselectivity (Table 1, entry 8). Conduct-
addition[16] and intramolecular cyclization[17] with various nucle-
ophilic reagents. In this field, alkyne could serve as
a
nucleophile to react with N-acyliminium ions affording impor-
[18a]
tant organic intermediates. For example, SnCl4
or TMSX[18b]
could lead to intramolecular cyclization of alkyne group with
the in situ generated iminium ion (Figure 3a and Figure 3b). Our
group also established a stereoselective approach to pyrido and
pyrrolo[1,2-c][1,3]oxazin-1-ones skeletons through the intermo-
lecular addition cyclization of triple bond to N-acyliminium ions
process (Figure 3c).[19] Interestingly, two different kinds of
nucleophilic reagents, ynamides and alkynes, could afford the
desired products with different configurations in this process.
Encouraged by these results, we envisioned that similar chiral
N-acyliminium ions with styrene acrylic framework could
potentially produce chiral isoindolinones. Herein we report our
results of TiCl4-mediated reactions of N,O-acetals 7a–7c, in
which the chiral phenyl glycine alcohol unit could control the
stereochemistry of addition-chlorination process with terminal
alkynes 8 (Figure 3d).
°
ing the reaction at lower temperature of À 78 C not only failed
to improve the diastereoselectivity, but also led to a significant
decrease in yield (Table 1, entry 9). Delightfully, when 1.5 equiv.
TiCl4 was used, the desired 9a was isolated in 72% yield with
91:9 diastereoselectivity (Table 1, entry 10). Further dropping
the loading of TiCl4 to 1.0 equiv. resulted in lower yield (Table 1,
entry 11). Other solvents (MeCN, THF) were also screened,
which turned out to be incompatible for this transformation
(Table 1, entries 12–13).
With the above identified optimized reaction conditions,
N,O-acetal 7a with different substituted terminal alkynes 8a–8t
were examined and the results were summarized in Scheme 1.
First, para substituted phenylacetylenes 8a–8i could afford the
desired products 9a–9i in moderate yields, with the diaster-
eoselectivities going up to 95:5. Regarding different substitu-
tions at the para position of phenylacetylenes, halogen or
electron withdrawing groups (such as CF3) offered better yields
of the desired products 9b–9e than alkyl and methoxy groups
(products 9f–9i, Scheme 1). Ortho substituted phenylacetylenes
8j–8l could afford the desired products 9j–9l in 64–75% yields
with good diastereoselectivities. Several meta substituted
phenylacetylenes 8m–8p were also examined, and the sub-
stitutions (methyl, methoxy and halogen) did not affect the
yields and diastereoselectivities of the products 9m–9p. β-
Results and Discussion
Our investigation started with the reaction of N,O-acetal 7a,
which was readily prepared according to the known
Table 1. Optimization of reaction conditions.
Entries[a]
Lewis acid(eq)
Solvent
Y%[c]
Z:E[d]
Dr[e]
1
2
3
4
5
6
7
8
–
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
MeCN
THF
NR
Complex
NR
NR
NR
NR
62
68
33
72
53
trace
trace
–
–
–
–
–
–
–
–
–
–
–
–
TMSOTf(2.0)
AuCl3(0.1)
TMSCl(2.0)
ZnCl2(2.0)
AlCl3(2.0)
SnCl4(2.0)
TiCl4(2.0)
TiCl4(2.0)
TiCl4(1.5)
TiCl4(1.0)
TiCl4(1.5)
TiCl4(1.5)
58:42
76:24
81:19
90:10
88:12
–
62:38
85:15
86:14
91:9
91:9
–
9[b]
10
11
12
13
–
–
[a] The reactions were performed with Lewis acid, N,O-acetal (0.79 mmol)
°
and alkyne (1.19 mmol) in dry DCM (5 mL) at À 45 C to room temperature
°
for 4 h; [b] The mixture was treated at À 78 C for 12 h; [c] Isolated yield; [d]
Z:E ratio was determined by HPLC of crude products; [e] dr was
determined by HPLC of crude products.
Figure 3. The reaction of alkynes with N-acyliminium ions.
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crystallographic analysis of compounds 9j and 9p (The
supplementary crystallographic data of 9j and 9p can be
obtained in the Supporting Information). The absolute config-
uration of (R,E,R)-9p was determined by ECD experiments (see
supporting information). The absolute configurations of (S,Z,R)-
9p and (S,E,R)-9p were elucidated by quantum chemical
calculations (see supporting information).[21]
Next, we turned our attention to investigate the scope and
limitation for the reactions of different substituted N,O-acetals
7b–7c with different substituted alkynes 8 (Scheme 2). First,
the reaction of chlorinated N,O-acetal 7b with different
substituted alkynes were examined. The results showed that
the substitution of chlorine atoms on N,O-acetals has a little
effect on the yield and diastereoselectivity of the product. The
desired 10a–10f were obtained in moderate yields and good
diastereoselectivities. It is worth mentioning that 3-ethynylth-
iophene could also react with 7b to give the desired 10g in
45% yield, but the diastereoselectivity of 10g was slightly lower
(dr=84:16). Other 5,6-dimethoxy substituted N,O-acetal 7c
could also react with different substituted alkynes, affording the
desired 11a–11f, respectively, in moderate yields and good
diastereoselectivities.
On the basis of our experimental results, a possible
mechanism was illustrated in Figure 4. First, TiCl4 coordinated
Scheme 1. The reactions of N,O-acetal 7a with different terminal alkynes.
a The reactions were performed with TiCl4 (1.19 mmol), N,O-acetal
°
(0.79 mmol) and alkyne (1.19 mmol) in dry DCM (5 mL) at À 45 C-room
temperature for 4 h; b Isolated yield; c Z:E was determined by HPLC of crude
products; d dr was determined by HPLC of crude products. e 9p (1.30 g, 67%
yield) was obtained with 7a (4.74 mmol), 8p (7.14 mmol), and TiCl4
°
(7.14 mmol) in dry DCM (15 mL) at À 45 C to rt for 4 h.
Naphthalene acetylene 8q also worked well, leading to the
desired product 9q in moderate yield and diastereoselectivity.
It was worth mentioning that alkyl substituted acetylenes
(cyclopropylacetylene 8r and 1-heptyne 8s) could also produce
the desired 9r–9s in moderate yields and diastereoselectivities.
In addition, heterocycle substituted acetylene, 2-thiophene
acetylene 8t, could react with N,O-acetal 7a to afford the
desired 9t in 73% yield with good diastereoselectivity (dr=
95:5). Unfortunately, the heterocycle 3-ethynylpyridine cannot
react. The chemical structures and relative stereochemistry of
9a–9t were unambiguously confirmed based on the X-ray
Scheme 2. The reactions of N,O-acetal 7a with different terminal alkynes.
a The reactions were performed with TiCl4 (1.19 mmol), N,O-acetal
°
(0.79 mmol) and alkyne (1.19 mmol) in dry DCM (5 mL) at À 45 C-room
temperature for 4 h; b Isolated yield; c Z:E was determined by HPLC of crude
products; d dr was determined by HPLC of crude products.
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saturated aqueous solution of NaHCO3 and extracted with EtOAc
for three times. The combined organic layers were washed with
brine and dried over anhydrous Na2SO4. Filtered and concentrated
under reduced pressure, the residue was purified by chromatog-
raphy on silica gel (PE/EA=2:1) to give the desired product 9–11.
(R)-3-((Z)-2-Chloro-2-phenylvinyl)-2-((R)-2-hydroxy-1-phenylethyl)
°
isoindolin-1-one (9a). White solid (222 mg, 72%), mp 173–175 C;
½a�2D6 =À 109.8 (c 1.00, CHCl3); IR (film): νmax 3055, 2926, 1669, 1467,
1
1394, 1220, 1071, 749, 696 cmÀ 1; H NMR (400 MHz, CDCl3) δ 7.90–
7.84 (m, 1H), 7.55–7.45 (m, 4H), 7.43–7.39 (m, 1H), 7.37–7.25 (m, 8H),
5.78 (d, J=9.2 Hz, 1H), 5.66 (d, J=8.8 Hz, 1H), 4.95–4.88 (m, 1H),
4.57–4.47 (m, 1H), 4.34 (brs, 1H), 4.20–4.13 (m, 1H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 170.0, 144.1, 138.7, 138.1, 136.6, 132.5,
132.3, 129.8, 129.1, 129.0, 128.7, 128.2, 128.0, 126.8, 124.1, 123.9,
123.3, 64.0, 62.0, 60.8 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd for
C24H20ClNO2Na+, 412.1075, found 412.1073.
Figure 4. Proposed mechanism for the formation of 2-chloro-2-substituted
(R)-3-((Z)-2-Chloro-2-(4-fluorophenyl)vinyl)-2-((R)-2-hydroxy-1-
phenylethyl)isoindolin-1-one (9b). White solid (235 mg, 73%), mp
isoindolin-1-ones.
161–163 C; ½a�2D5 =À 79.8 (c 1.00, CHCl3); IR (film): νmax 3059, 2920,
°
1671, 1598, 1502, 1395, 1230, 1159, 749, 699 cmÀ 1
;
1H NMR
(400 MHz, CDCl3) δ 7.85–7.78 (m, 1H), 7.51–7.33 (m, 7H), 7.31–7.20
(m, 3H), 7.05–6.93 (m, 2H), 5.75–5.68 (m, 1H), 5.66–5.60 (m, 1H),
5.13–5.03 (m, 1H), 4.56–4.49 (m, 1H), 4.23–4.15 (m, 1H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 169.8, 163.4 (d, J=248.8 Hz), 143.8, 137.8,
137.4, 132.6 (d, J=3.4 Hz), 132.3, 132.0, 129.0, 128.8, 128.6, 128.5,
128.1, 127.7, 124.0, 123.7 (d, J=1.2 Hz), 123.0, 115.4 (d, J=21.8 Hz),
63.8, 61.8, 60.5 ppm; 19F NMR (376 MHz, CDCl3) δ À 111.1 ppm;
HRMS (ESI) m/z: [M+Na]+ Calcd for C24H19FClNO2Na+, 430.0981,
found 430.0979.
with the oxygen of N,O-acetal 7a to form an intermediate A,
which readily underwent ring-opening to generate
a N-
acyliminium ion B. Subsequently, the formation of alternative
ring, due to the coordination of the carbonyl group with
titanium, resulted in nucleophilic attack of the phenylacetylene
substrate predominantly from the less hindered face, and the
resultant cationic intermediate C further reacted with chloride
to give intermediate, which ultimately led to the desired (R)-3-
((Z)-2- chloro-2-phenylvinyl)-2-((R) À 2-hydroxy-1- phenylethyl)
isoindolin À 1-one 9a under acidic conditions.
(R)-3-((Z)-2-(4-Bromophenyl)-2-chlorovinyl)-2-((R)-2-hydroxy-1-
phenylethyl)isoindolin-1-one (9c). White solid (277 mg, 75%), mp
169–171 C; ½a�2D4 =À 91.9 (c 0.57, CHCl3); IR (film): νmax 3057, 2924,
°
1669, 1482, 1465, 1392, 1349, 1071, 749, 698 cmÀ 1
;
1H NMR
(400 MHz, CDCl3) δ 7.90–7.85 (m, 1H), 7.54–7.46 (m, 4H), 7.41–7.38
(m, 1H), 7.35–7.26 (m, 7H), 5.76 (d, J=8.8 Hz, 1H), 5.65 (d, J=9.2 Hz,
1H), 4.93 (dd, J=8.4, 3.6 Hz, 1H), 4.51 (dd, J=12.0, 9.6 Hz, 1H), 4.24–
4.04 (m, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.7, 143.6,
137.8, 137.2, 135.3, 132.3, 132.0, 131.6, 129.0, 128.8, 128.1 (2 C),
127.7, 124.5, 124.0, 123.9, 123.0, 63.7, 61.6, 60.4 ppm; HRMS (ESI)
m/z: [M+Na]+ Calcd for C24H19ClBrNO2Na+, 490.0180, found
490.0181.
Conclusion
In summary, we established a diastereoselective approach for
the synthesis of 2-substituted isoindolin-1-ones skeleton. The
reaction of N,O-acetals 7a–7c with terminal alkynes 8 went
through
a TiCl4 mediated successive addition-chlorination
process. As a result, a series of 2-substituted isoindolin-1-ones
9–11 were obtained in moderate to good yields and diaster-
eoselectivities under mild reaction conditions.
(R)-3-((Z)-2-Chloro-2-(4-chlorophenyl)vinyl)-2-((R)-2-hydroxy-1-
phenylethyl)isoindolin-1-one (9d). White solid (258 mg, 77%), mp
150–152 C; ½a�2D4 =À 89.1 (c 0.32, CHCl3); IR (film): νmax 3061, 2920,
°
1673, 1491, 1470, 1395, 1349, 1088, 749, 699 cmÀ 1
;
1H NMR
(400 MHz, CDCl3) δ 7.90–7.81 (m, 1H), 7.55–7.46 (m, 2H), 7.40–7.35
(m, 3H), 7.33–7.24 (m, 7H), 5.77–5.69 (m, 1H), 5.66–5.59 (m, 1H),
4.97–4.88 (m, 1H), 4.56–4.43 (m, 1H), 4.257–4.18 (m, 2H) ppm; 13C
{1H} NMR (100 MHz, CDCl3) δ 169.7, 143.6, 137.8, 137.2, 135.3, 132.3,
132.0, 131.6, 129.0, 128.8, 128.1, 127.7, 124.5, 124.0, 123.9, 123.0,
63.6, 61.5, 60.4 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd for
C24H19Cl2NO2Na+, 468.1701, found 468.1705.
Experimental Section
General: Reactions were monitored by thin layer chromatography
(TLC) on glass plates coated with silica gel with a fluorescent
indicator. Flash chromatography was performed on silica gel (300–
400) with petroleum/EtOAc as the eluent. Optical rotations were
measured on a polarimeter with a sodium lamp. HRMS was
conducted on Thermo Scientific LTQ Orbitrap XL apparatus. IR
spectra were record using a film on a Fourier transform infrared
spectrometer. NMR spectra were recorded at 400 MHz, and
chemical shifts are reported in (ppm) referenced to an internal TMS
standard for H NMR and CDCl3 (77.16 ppm) for 13C{1H} NMR. The
N,O-acetals were synthesized according to the known method.[13,20]
(R)-3-((Z)-2-Chloro-2-(4-(trifluoromethyl)phenyl)vinyl)-2-((R)-2-
hydroxy-1-phenylethyl)isoindolin-1-one
(9e).
Colorless
oil
(260 mg, 72%); ½a�2D4 =À 79.2 (c 0.38, CHCl3); IR (film): νmax 2920,
2849, 1669, 1465, 1406, 1322, 1170, 1131, 1066, 749, 698 cmÀ 1; H
1
NMR (400 MHz, CDCl3) δ 7.90–7.86 (m, 1H), 7.61–7.49 (m, 6H), 7.42–
7.39 (m, 1H), 7.37–7.27 (m, 5H), 5.84 (d, J=8.8 Hz, 1H), 5.70 (d, J=
9.2 Hz, 1H), 4.99 (d, J=8.8, 4.4 Hz, 1H), 4.59–4.47 (m, 1H), 4.22–4.14
(m, 1H), 4.07 (brs, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.8,
143.4, 139.7, 137.7, 136.7, 132.4, 132.0, 129.1, 128.9, 128.2, 127.7,
127.0, 126.2, 125.5, 125.4, 124.1, 123.0, 63.7, 61.1, 60.3 ppm; 19F NMR
General Procedure for Synthesis of 9–11. To a solution of N,O-
acetal 7 (0.79 mmol ) and 8 (1.19 mmol) in anhydrous DCM (5 mL)
°
was treated with TiCl4 (1.19 mmol) at À 45 C under an argon
atmosphere. The rection mixture was slowly warmed to room
temperature and stirred for 4 h. The mixture was quenched with
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(376 MHz, CDCl3) δ À 63.2 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd for
(ESI) m/z: [M+Na]+ Calcd for C24H19FClNO2Na+, 430.0981, found
430.0978.
C25H19ClF3NO2Na+, 480.0949, found 480.0950.
(R)-3-((Z)-2-Chloro-2-(p-tolyl)vinyl)-2-((R)-2-hydroxy-1-phenyleth-
(R)-3-((Z)-2-Chloro-2-(o-tolyl)vinyl)-2-((R)-2-hydroxy-1-phenyleth-
yl)isoindolin-1-one (9k). Colorless oil (204 mg, 64%); ½a�2D3 =À 25.4
(c 1.00, CHCl3); IR (film): νmax 3057, 2924, 1671, 1467, 1395, 1348,
1239, 1076, 749, 696 cmÀ 1; 1H NMR (400 MHz, CDCl3) δ 7.91–7.85 (m,
1H), 7.61–7.56 (m, 1H), 7.53–7.47 (m, 1H), 7.39–7.25 (m, 6H), 7.22–
7.14 (m, 3H), 5.58 (d, J=8.0 Hz, 1H), 5.44 (d, J=8.0 Hz, 1H), 4.88–
4.82 (m, 1H), 4.59–4.51 (m, 1H), 4.44 (brs, 1H), 4.19–4.12 (m, 1H),
2.41 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.8, 143.9,
138.6, 137.9, 135.7, 132.4, 132.1, 130.6, 129.4, 129.1, 128.9 (2 C),
128.1, 127.7, 126.9, 125.9, 124.0, 122.8, 64.1, 62.7, 60.5, 20.0 ppm;
HRMS (ESI) m/z: [M+Na]+ Calcd for C25H22ClNO2Na+, 426.1231,
found 426.1230.
°
yl)isoindolin-1-one (9f). White solid (210 mg, 66%), mp 148–150 C;
½a�2D4 =À 85.7 (c 1.00, CHCl3); IR (film): νmax 3059, 2920, 1669, 1598,
1
1467, 1392, 1350, 1071, 747, 696 cmÀ 1; H NMR (400 MHz, CDCl3) δ
7.91–7.86 (m, 1H), 7.56–7.47 (m, 2H), 7.42–7.37 (m, 3H), 7.34–7.25
(m, 5H), 7.19–7.13 (m, 2H), 5.75 (d, J=8.8 Hz, 1H), 5.63 (d, J=9.2 Hz,
1H), 4.91–4.82 (m, 1H), 4.50 (dd, J=11.6, 8.4 Hz, 1H), 4.33 (brs, 1H),
4.15 (dd, J=12.0, 3.6 Hz, 1H), 2.37 (s, 3H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ 169.8, 144.0, 139.9, 138.8, 137.9, 133.7, 132.3,
132.1, 129.2, 128.9, 128.8, 128.0, 127.7, 126.5, 123.9, 123.1, 122.5,
64.0, 62.1, 60.7, 21.2 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd for
C25H22ClNO2Na+, 426.1231, found 426.1230.
(R)-3-((Z)-2-(4-Butylphenyl)-2-chlorovinyl)-2-((R)-2-hydroxy-1-phe-
(R)-3-((Z)-2-Chloro-2-(2-chlorophenyl)vinyl)-2-((R)-2-hydroxy-1-
phenylethyl)isoindolin-1-one (9l). Colorless oil (251 mg, 75%);
½a�2D1 =À 18.5 (c 1.00, CHCl3); IR (film): νmax 3059, 2922, 1671, 1467,
23
nylethyl)isoindolin-1-one (9g). Colorless oil (186 mg, 53%); ½a�D
=
À 76.0 (c 1.00, CHCl3); IR (film): νmax 3057, 2953, 2927, 1676, 1467,
1
1
1395, 1355,1071, 752, 694 cmÀ 1; H NMR (400 MHz, CDCl3) δ 7.89–
1449, 1397, 1237, 1073, 749, 699 cmÀ 1; H NMR (400 MHz, CDCl3) δ
7.83 (m, 1H), 7.52–7.43 (m, 2H), 7.40–7.23 (m, 8H), 7.17–7.12 (m, 2H),
5.74 (d, J=9.2 Hz, 1H), 5.67 (d, J=9.2 Hz, 1H), 4.93 (dd, J=8.4,
4.0 Hz, 1H), 4.51 (dd, J=12.0, 8.8 Hz, 1H), 4.16 (dd, J=12.4, 4.0 Hz,
1H), 2.63–2.57 (m, 2H), 1.62–1.54 (m, 2H), 1.37–1.31 (m, 2H), 0.94–
0.90 (m, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.7, 144.9,
144.0, 138.7, 138.0, 133.8, 132.2, 132.0, 128.8, 128.7, 128.0, 127.7,
126.5, 123.9, 123.0, 122.6, 63.8, 61.8, 60.7, 35.3, 33.4, 22.3, 13.9 ppm;
HRMS (ESI) m/z: [M+Na]+ Calcd for C28H28ClNO2Na+, 468.1701,
found 468.1704.
7.94–7.89 (m, 1H), 7.59–7.49 (m, 4H), 7.44–7.41 (m, 1H), 7.39–7.29
(m, 7H), 5.80 (d, J=9.2 Hz, 1H), 5.66 (d, J=9.2 Hz, 1H), 4.84 (dd, J=
8.8, 4.0 Hz, 1H), 4.59–4.50 (m, 1H), 4.19 (dd, J=12.0, 3.6 Hz, 1H),
4.08 (brs, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.8, 143.5,
137.9, 136.9, 135.5, 132.6, 132.4, 132.1, 130.6 (2 C), 130.1, 129.0,
128.8, 128.6, 128.1, 127.8, 126.9, 123.9, 123.1, 64.1, 62.6, 60.3 ppm;
HRMS (ESI) m/z: [M+Na]+ Calcd for C25H22ClNO2Na+, 446.0685,
found 446.0682.
(R)-3-((Z)-2-Chloro-2-(m-tolyl)vinyl)-2-((R)-2-hydroxy-1-phenyleth-
yl)isoindolin-1-one (9m). White solid (226 mg, 71%), mp 163–
(R)-3-((Z)-2-(4-(tert-Butyl)phenyl)-2-chlorovinyl)-2-((R)-2-hydroxy-
1-phenylethyl)isoindolin-1-one (9h). Colorless oil (200 mg, 57%);
½a�2D4 =À 83.4 (c 1.00, CHCl3); IR (film): νmax 2963, 2865, 1673, 1467,
165 C; ½a�2D4 =À 93.3 (c 1.00, CHCl3); IR (film): νmax 3057, 2920, 1669,
°
1
1467, 1392, 1349, 1071, 747, 698 cmÀ 1; H NMR (400 MHz, CDCl3) δ
1
1398, 1349,1076, 751, 694 cmÀ 1; H NMR (400 MHz, CDCl3) δ 7.92–
7.90–7.85 (m, 1H), 7.55–7.46 (m, 2H), 7.42–7.38 (m, 1H), 7.37–7.23
(m, 8H), 7.19–7.14 (m, 1H), 5.76 (d, J=9.2 Hz, 1H), 5.66 (d, J=9.2 Hz,
1H), 4.96–4.88 (m, 1H), 4.55–4.45 (m, 1H), 4.34 (brs, 1H), 4.23–4.11
(m, 1H), 2.36 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.8,
144.0, 138.7, 138.2, 137.9, 136.4, 132.3, 132.0, 130.4, 128.9, 128.8,
128.4, 128.0, 127.7, 127.2, 123.9, 123.8, 123.4, 123.0, 63.8, 61.8, 60.6,
21.3 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd for C25H22ClNO2Na+,
426.1231, found 426.1230.
7.83 (m, 1H), 7.52–7.44 (m, 4H), 7.40–7.30 (m, 8H), 5.78 (d, J=9.2 Hz,
1H), 5.61 (d, J=9.2 Hz, 1H), 4.87–4.77 ( m, 1H), 4.53–4.44 (m, 1H),
4.44–4.39 (m, 1H), 4.17–4.09 (m, 1H), 1.31 (s, 9H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ 169.8, 153.2, 144.0, 138.8, 137.8, 133.5, 132.3,
132.1, 128.9, 128.8, 128.0, 127.7, 126.3, 125.5, 123.9, 123.1, 122.5,
64.1, 62.3, 60.8, 34.7, 31.2 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd for
C28H28ClNO2Na+, 468.1701, found 468.1705.
(R)-3-((Z)-2-Chloro-2-(4-methoxyphenyl)vinyl)-2-((R)-2-hydroxy-1-
phenylethyl)isoindolin-1-one (9i). White solid (215 mg, 65%), mp
(R)-3-((Z)-2-Chloro-2-(3-methoxyphenyl)vinyl)-2-((R)-2-hydroxy-1-
phenylethyl)isoindolin-1-one (9n). White solid (205 mg, 62%), mp
147–149 C; ½a�2D3 =À 109.2 (c 0.50, CHCl3); IR (film): νmax 3055, 2918,
139–141 C; ½a�2D1 =À 88.6 (c 1.00, CHCl3); IR (film): νmax 3061, 2928,
°
°
1669, 1604, 1507, 1255, 1178, 1029, 747, 696 cmÀ 1
;
1H NMR
1596, 1470, 1394, 1265, 1048, 779, 747, 694 cmÀ 1; 1H NMR (400 MHz,
CDCl3) δ 7.90–7.85 (m, 1H), 7.55–7.47 (m, 2H), 7.43–7.39 (m, 1H),
7.36–7.23 (m, 6H), 7.09–7.02 (m, 2H), 6.93–6.88 (m, 1H), 5.79 (d, J=
9.2 Hz, 1H), 5.65 (d, J=9.2 Hz, 1H), 4.90 (dd, J=8.4, 4.0 Hz, 1H),
4.55–4.46 (m, 1H), 4.34 (brs, 1H), 4.16 (dd, J=8.0, 3.6 Hz, 1H), 3.81 (s,
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.5, 159.4, 143.6, 138.0,
137.6 (2 C), 132.0, 131.8, 129.3, 128.7, 128.5, 127.8, 127.5, 123.7,
122.8, 118.8, 114.9, 112.2, 63.5, 61.6, 60.3, 55.2 ppm; HRMS (ESI)
m/z: [M+Na]+ Calcd for C25H22ClNO3Na+, 442.1180, found
442.1181.
(400 MHz, CDCl3) δ 7.91–7.87 (m, 1H), 7.57–7.49 (m, 2H), 7.47–7.39
(m, 3H), 7.36–7.27 (m, 5H), 6.89–6.84 (m, 2H), 5.69 (d, J=9.2 Hz, 1H),
5.64 (d, J=8.8 Hz, 1H), 4.86 (dd, J=8.4, 4.0 Hz, 1H), 4.50 (dd, J=
12.0, 8.4 Hz, 1H), 4.15 (dd, J=12.0, 4.0 Hz, 1H), 3.83 (s, 3H) ppm; 13C
{1H} NMR (100 MHz, CDCl3) δ 169.8, 160.7, 144.2, 138.5, 137.9, 132.3,
132.1, 129.0 (2 C), 128.8, 128.7, 128.0, 127.7, 123.9, 123.1, 121.5,
113.8, 64.0, 62.1, 60.8, 55.4 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd
for C25H22ClNO3Na+, 442.1180, found 442.1179.
(R)-3-((Z)-2-Chloro-2-(2-fluorophenyl)vinyl)-2-((R)-2-hydroxy-1-
phenylethyl)isoindolin-1-one (9j). White solid (232 mg, 72%), mp
(R)-3-((Z)-2-(3-Bromophenyl)-2-chlorovinyl)-2-((R)-2-hydroxy-1-
phenylethyl)isoindolin-1-one (9o). Yellow oil (261 mg, 71%);
½a�2D4 =À 304.0 (c 0.50, CHCl3); IR (film): νmax 3059, 2922, 1669, 1472,
148–150 C; ½a�2D4 =À 54.3 (c 0.40, CHCl3); IR (film): νmax 3059, 2922,
°
1671, 1486, 1449, 1397, 1237, 1073, 749, 699 cmÀ 1
;
1H NMR
1
(400 MHz, CDCl3) δ 7.90–7.83 (m, 1H), 7.57–7.43 (m, 4H), 7.38–7.26
(m, 6H), 7.19–7.13 (m, 1H), 7.12–7.05 (m, 1H), 5.80 (d, J=9.2 Hz, 1H),
5.61 (d, J=9.2 Hz, 1H), 4.90–4.82 (m, 1H), 4.58–4.44 (m, 2H), 4.21–
4.12 (m, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.8, 159.3 (d,
J=250.5 Hz), 143.6, 137.8, 132.3, 132.1, 132.0 (d, J=2.1 Hz), 131.1
(d, J=8.6 Hz), 130.2 (d, J=1.7 Hz), 129.0, 128.8, 128.0, 127.8, 125.3,
125.2, 124.2 (d, J=3.7 Hz), 123.9, 123.0, 116.2 (d, J=22.2 Hz), 64.0,
62.5, 60.7 ppm; 19F NMR (376 MHz, CDCl3) δ À 113.2 ppm; HRMS
1397, 1349, 1215, 1068, 749, 692 cmÀ 1; H NMR (400 MHz, CDCl3) δ
7.91–7.83 (m, 1H), 7.55–7.45 (m, 4H), 7.43–7.39 (m, 1H), 7.38–7.25
(m, 8H), 5.78 (d, J=9.2 Hz, 1H), 5.66 (d, J=8.8 Hz, 1H), 4.92 (dd, J=
8.0, 3.6 Hz, 1H), 4.56–4.47 (m, 1H), 4.34 (brs, 1H), 4.20–4.12 (m, 1H)
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.8, 144.0, 138.5, 137.9,
136.4, 132.3, 132.1, 129.6, 128.9, 128.8, 128.5, 128.0, 127.7, 126.6,
123.9, 123.7, 123.1, 63.8, 61.8, 60.6 ppm; HRMS (ESI) m/z: [M+Na]+
Calcd for C25H22ClNO3Na+, 490.0180, found 490.0181.
Eur. J. Org. Chem. 2021, 2625–2633
www.eurjoc.org
2629
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100368
(R)-3-((Z)-2-Chloro-2-(3-fluorophenyl)vinyl)-2-((R)-2-hydroxy-1-
132.9, 132.3, 132.1, 128.9, 128.8, 128.6, 128.2, 128.1, 127.8, 127.6,
127.2, 126.9, 126.7, 124.0 (2 C), 123.5, 123.1, 63.9, 62.0, 60.7 ppm;
HRMS (ESI) m/z: [M+Na]+ Calcd for C28H22ClNO2Na+, 462.1231,
found 462.1231.
phenylethyl)isoindolin-1-one (9p). White solid (232 mg, 72%), mp
157–159 C; ½a�2D4 =À 97.4 (c 0.50, CHCl3); IR (film): νmax 3061, 2922,
°
1669, 1582, 1392, 1263, 1155, 1073, 749, 699 cmÀ 1
;
1H NMR
(400 MHz, CDCl3) δ 7.92–7.82 (m, 1H), 7.56–7.47 (m, 2H), 7.42–7.37
(m, 1H), 7.36–7.22 (m, 7H), 7.21–7.13 (m, 1H), 7.10–7.01 (m, 1H), 5.79
(d, J =8.8 Hz, 1H), 5.66 (d, J=8.8 Hz, 1H), 4.94 (dd, J=8.8, 4.4 Hz,
1H), 4.58–4.47 (m, 1H), 4.20–4.14 (m, 1H), 4.13–4.06 (m, 1H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 169.7, 162.6 (d, J=245.2 Hz), 143.6,
138.6 (d, J=7.9 Hz), 137.8, 136.8 (d, J=2.7 Hz), 132.3, 132.0, 130.0
(d, J=8.3 Hz), 129.0, 128.8, 128.1, 127.7, 125.1, 124.0, 123.0, 122.2
(d, J=2.7 Hz), 116.5 (d, J=21.2 Hz), 113.9 (d, J=23.7 Hz), 63.6, 61.6,
60.3 ppm; 19F NMR (376 MHz, CDCl3) δ À 112.8 ppm; HRMS (ESI) m/z:
[M+Na]+ Calcd for C24H19FClNO2Na+, 430.0981, found 430.0980.
(R)-3-((Z)-2-Chloro-2-cyclopropylvinyl)-2-((R)-2-hydroxy-1-phenyl-
ethyl)isoindolin-1-one (9r). White solid (142 mg, 51%), mp 169–
171 C; ½a�2D4 =À 60.1 (c 0.40, CHCl3); IR (film): νmax 3059, 2922, 1671,
°
1467, 1397, 1348, 1208, 1073, 749, 699 cmÀ 1
;
1H NMR (400 MHz,
CDCl3) δ 7.88–7.83 (m, 1H), 7.54–7.46 (m, 2H), 7.34–7.27 (m, 6H),
5.42 (d, J=9.2 Hz, 1H), 5.24 (d, J=9.2 Hz, 1H), 4.76 (dd, J=7.6,
3.6 Hz, 1H), 4.52–4.38 (m, 2H), 4.17–4.10 (m, 1H), 1.74–1.67 (m, 1H),
0.83–0.73 (m, 4H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.7,
144.4, 143.2, 137.9, 132.1, 132.0, 128.7 (2 C), 127.9, 127.7, 123.7,
123.0, 120.3, 64.1, 62.0, 60.2, 18.7, 6.4, 6.1 ppm; HRMS (ESI) m/z: [M
+Na]+ Calcd for C21H20ClNO2Na+, 376.1075, found 376.1075.
(S)-3-((Z)-2-Chloro-2-(3-fluorophenyl)vinyl)-2-((R)-2-hydroxy-1-
phenylethyl)isoindolin-1-one ((S,Z,R)-9p). ½a�2D3 =À 125.2 (c 1.00,
CHCl3); IR (film): νmax 3061, 2922, 1669, 1582, 1392, 1263, 1155, 1073,
(R)-3-((Z)-2-Chlorohept-1-en-1-yl)-2-((R)-2-hydroxy-1-phenylethyl)
isoindolin-1-one (9s). Colorless oil (195 mg, 67%); ½a�2D4 =À 27.5 (c
1.00, CHCl3); IR (film): νmax 3059, 2922, 1671, 1469, 1395, 1352, 1130,
1
749, 699 cmÀ 1; H NMR (400 MHz, CDCl3) δ 7.92–7.86 (m, 1H), 7.62–
751 (m, 2H), 7.37–7.33 (m, 1H), 7.24–7.14 (m, 4H), 7.12–7.05 (m, 2H),
7.04–6.92 (m, 3H), 5.70 (d, J=10.4 Hz, 1H), 4.94 (d, J=10.4 Hz, 1H),
4.70 (dd, J=8.0, 3.6 Hz, 1H), 4.58–4.48 (m, 1H), 4.44–4.34 (m, 1H),
4.16–4.07 (m, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.5, 162.4
(d, J=247.1 Hz), 143.3, 137.43 (d, J=7.7 Hz), 137.42, 137.1 (d, J=
2.2 Hz), 132.4, 132.1, 130.2 (d, J=8.4 Hz), 129.2, 128.7, 128.0, 127.1,
126.6, 124.1, 124.0 (d, J=3.0 Hz), 122.9, 116.6 (d, J=21.0 Hz, 1H),
115.7 (d, J=22.7 Hz), 64.4, 63.1, 60.1 ppm; 19F NMR (376 MHz,
1
1073, 749, 699 cmÀ 1; H NMR (400 MHz, CDCl3) δ 7.90–7.87 (m, 1H),
7.58–7.50 (m, 2H), 7.37–7.28 (m, 4H), 7.25–7.23 (m, 2H), 5.31 (d, J=
10.4 Hz, 1H), 4.97 (d, J=10.0 Hz, 1H), 4.80 (s, 1H), 4.68 (dd, J=7.6,
3.2 Hz, 1H), 4.43–4.35 (m, 1H), 4.17–4.10 (m, 1H), 2.22–2.14 (m, 2H),
1.59–1.51 (m, 2H), 1.27–1.23 (m, 2H), 0.90–0.84 (m, 3H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 169.7, 144.0, 142.4, 138.0, 132.5, 132.2,
129.1, 129.0, 128.2, 127.5, 124.1, 123.8, 123.0, 64.7, 63.2, 60.0, 34.2,
31.2, 27.8, 22.4, 14.0 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd for
C23H26ClNO2Na+, 406.1544, found 406.1543.
CDCl3)
δ
À 113.2 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd for
C24H19ClFNO2Na+ 430.0981, found 430.0988.
(R)-3-((Z)-2-Chloro-2-(thiophen-3-yl)vinyl)-2-((R)-2-hydroxy-1-phe-
nylethyl)isoindolin-1-one (9t). White solid (228 mg, 73%), mp 165–
(S)-3-((E)-2-Chloro-2-(3-fluorophenyl)vinyl)-2-((R)-2-hydroxy-1-
phenylethyl)isoindolin-1-one ((S,E,R)-9p). ½a�2D3 = +159.0 (c 1.00,
CHCl3); IR (film): νmax 3061, 2922, 1669, 1582, 1392, 1263, 1155, 1073,
167 C; ½a�2D4 =À 107.1 (c 1.00, CHCl3); IR (film): νmax 3030, 2922, 1671,
°
1624, 1469, 1397, 1352, 1073, 749, 699 cmÀ 1
;
1H NMR (400 MHz,
1
749, 699 cmÀ 1; H NMR (400 MHz, CDCl3) δ 7.90–7.84 (m, 1H), 7.55–
CDCl3) δ 7.91–7.86 (m, 1H), 7.56–7.48 (m, 2H), 7.41–7.37 (m, 1H),
7.35–7.26 (m, 7H), 7.03–6.99 (m, 1H), 5.75 (d, J=9.2 Hz, 1H), 5.57 (d,
J=9.2 Hz, 1H), 4.86 (dd, J=8.0, 3.6 Hz, 1H), 4.52–4.43 (m, 1H), 4.33
(brs, 1H), 4.19–4.12 (m, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ
169.7, 143.7, 140.2, 137.8, 132.3, 132.0, 131.8, 128.9, 128.8, 128.0,
127.7, 127.6, 127.2, 127.1, 123.9, 123.1, 121.4, 64.0, 62.1, 60.4 ppm;
HRMS (ESI) m/z: [M+Na]+ Calcd for C22H18ClNO2SNa+, 418.0639,
found 418.0638.
7.46 (m, 2H), 7.41–7.26 (m, 6H), 7.25–7.20 (m, 1H), 7.05–7.00 (m, 2H),
6.96–6.90 (m, 1H), 5.74 (d, J=6.0 Hz, 1H), 5.71 (d, J=6.0 Hz, 1H),
5.16 (dd, J=5.6, 3.2 Hz, 1H), 4.40 (dd, J=8.0, 5.6 Hz, 1H), 4.20 (dd,
J=8.0, 3.2 Hz, 1H), 3.79 (brs, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
δ 169.9, 162.5 (d, J=245.1 Hz), 143.5, 138.7 (d, J=7.8 Hz), 138.0,
135.4, 132.3, 131.9, 129.9 (d, J=8.3 Hz), 129.0, 128.9, 128.0, 127.9,
125.7, 123.9, 122.9, 122.1 (d, J=2.4 Hz), 116.3 (d, J=21.1 Hz), 113.8
(d, J=23.6 Hz), 63.9, 61.9, 61.7 ppm; 19F NMR (376 MHz, CDCl3) δ
À 112.5 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd for C24H19ClFNO2Na+
430.0981, found 430.0981.
(R)-6-Chloro-3-((Z)-2-chloro-2-phenylvinyl)-2-((R)-2-hydroxy-1-
phenylethyl)isoindolin-1-one (10a). Colorless oil (214 mg, 64%);
½a�2D1 =À 52.4 (c 1.00, CHCl3); IR (film): νmax 3059, 2927, 1678, 1614,
(R)-3-((E)-2-Chloro-2-(3-fluorophenyl)vinyl)-2-((R)-2-hydroxy-1-
phenylethyl)isoindolin-1-one ((R,E,R)-9p). ½a�2D3 = +232.0 (c 0.50,
CHCl3); IR (film): νmax 3061, 2922, 1669, 1582, 1392, 1263, 1155, 1073,
1
1422, 1352, 1118, 1061, 762, 692 cmÀ 1; H NMR (400 MHz, CDCl3) δ
7.83–7.78 (m, 1H), 7.52–7.46 (m, 3H), 7.42–7.30 (m, 9H), 5.80–5.75
(m, 1H), 5.72–5.66 (m, 1H), 5.01–4.92 (m, 1H), 4.60–4.48 (m, 1H),
4.30–4.03 (m, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 168.7,
145.5, 138.9, 138.7, 137.7, 136.2, 130.5, 129.8, 129.5, 128.8, 128.5,
128.1, 127.7, 126.6, 125.1, 123.4, 123.0, 63.4, 61.5, 60.0 ppm; HRMS
(ESI) m/z: [M+Na]+ Calcd for C25H21Cl2NO2Na+, 446.0685, found
446.0686.
1
749, 699 cmÀ 1; H NMR (400 MHz, CDCl3) δ 7.89–7.85 (m, 1H), 7.61–
756 (m, 1H), 7.54–7.49 (m, 1H), 7.40–7.37 (m, 1H), 7.35–7.31 (m, 1H),
7.26–7.20 (m, 5H), 7.14–7.04 (m, 3H), 5.57 (d, J=6.8 Hz, 1H), 5.11
(dd, J=6.0 Hz, 3.6 Hz, 1H), 5.08 (d, J=7.2 Hz, 1H), 4.36 (dd, J=8.0,
6.0 Hz, 1H), 4.20 (dd, J=8.0, 3.6 Hz, 1H), 3.17 (brs, 1H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 169.6, 162.5 (d, J=246.8 Hz), 143.3, 137.6
(d, J=7.9 Hz), 137.2, 135.0, 132.3, 131.8, 130.4 (d, J=8.4 Hz), 129.1,
128.8, 128.0, 127.6, 124.1, 122.8, 116.7 (d, J=20.9 Hz), 115.7 (d, J=
(R)-6-Chloro-3-((Z)-2-chloro-2-(o-tolyl)vinyl)-2-((R)-2-hydroxy-1-
phenylethyl)isoindolin-1-one (10b). Colorless oil (238 mg, 69%);
½a�2D1 =À 47.3 (c 1.00, CHCl3); IR (film): νmax 3059, 2920, 1681, 1611,
22.5 Hz), 63.5, 60.2, 60.1 ppm; 19F NMR (376 MHz, CDCl3)
δ
À 111.0 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd for C24H19ClFNO2Na+
1420, 1389, 1352, 1297, 1063, 769, 694 cmÀ 1 1H NMR (400 MHz,
;
30.0981, found 430.0988.
CDCl3) δ 7.81–7.75 (m, 1H), 7.49–7.44 (m, 1H), 7.40–7.23 (m, 7H),
7.22–7.13 (m, 3H), 5.56 (d, J=8.8 Hz, 1H), 5.43 (d, J=9.2 Hz, 1H),
4.84 (dd, J=9.2, 4.0 Hz, 1H), 4.59–4.51 (m, 1H), 4.22–4.11 (m, 2H),
2.42 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 168.7, 145.5,
139.1, 138.7, 137.6, 135.6, 130.6, 129.5, 129.1, 128.9, 128.2, 127.6,
126.2, 126.0, 125.2, 123.2, 63.8, 62.5, 60.0, 20.0 ppm; HRMS (ESI)
m/z: [M+Na]+ Calcd for C25H21Cl2NO2Na+, 460.0842, found
460.0844.
(R)-3-((Z)-2-Chloro-2-(naphthalen-2-yl)vinyl)-2-((R)-2-hydroxy-1-
phenylethyl)isoindolin-1-one (9q). Colorless oil (222 mg, 64%);
½a�2D1 =À 143.8 (c 0.50, CHCl3); IR (film): νmax 3059, 2922, 1671, 1604,
1499, 1424, 1298, 1220, 1073, 749, 699 cmÀ 1 1H NMR (400 MHz,
;
CDCl3) δ 8.04–7.98 (m, 1H), 7.92–7.78 (m, 4H), 7.57–7.44 (m, 6H),
7.40–7.26 (m, 5H), 5.93 (d, J=9.2 Hz, 1H), 5.71 (d, J=9.2 Hz, 1H),
4.90–4.90 (m, 1H), 4.59–4.48 (m, 1H), 4.29–4.07 (m, 2H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 169.8, 143.9, 138.6, 137.9, 133.6, 133.5,
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°
(R)-6-Chloro-3-((Z)-2-chloro-2-(m-tolyl)vinyl)-2-((R)-2-hydroxy-1-
phenylethyl)isoindolin-1-one (10c). Colorless oil (228 mg, 66%);
½a�2D1 =À 40.8 (c 0.50, CHCl3); IR (film): νmax 3059, 2928, 1676, 1609,
70%), mp 143–145 C; ½a�D21 =À 75.9 (c 1.00, CHCl3); IR (film): νmax
1
3059, 2935, 1663, 1624, 1499, 1424, 1298, 1217, 759, 694 cmÀ 1; H
NMR (400 MHz, CDCl3) δ 7.54–7.49 (m, 1H), 7.40–7.28 (m, 9H), 6.82–
6.78 (m, 1H), 5.80 (d, J=9.2 Hz, 1H), 5.56 (d, J=9.2, 1H), 4.86 (dd,
J=8.0, 3.6 Hz, 1H), 4.47 (dd, J=12.4, 9.2 Hz, 1H), 4.16 (dd, J=12.0,
3.6 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 170.1, 153.3, 150.3, 138.4, 138.1, 137.6, 136.3, 129.7, 128.8,
128.5, 128.3, 127.9, 127.6, 126.6, 124.2, 124.0, 105.3, 104.8, 64.0,
61.9, 60.2, 56.4 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd for
C26H24ClNO4Na+, 450.1468, found 450.1468.
1
1425, 1392, 1352, 1065, 781, 694 cmÀ 1; H NMR (400 MHz, CDCl3) δ
7.80–7.76 (m, 1H), 7.47–7.44 (m, 1H), 7.39–7.37 (m, 1H), 7.34–7.24
(m, 8H), 7.20–7.17 (m, 1H), 5.73 (d, J=9.2 Hz, 1H), 5.64 (d, J=9.2 Hz,
1H), 4.92 (dd, J=8.8, 4.0 Hz, 1H), 4.56–4.45 (m, 1H), 4.21–4.01 (m,
2H), 2.36 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 168.7, 145.5,
139.2, 138.7, 138.3, 137.7, 136.2, 130.6, 130.5, 129.5, 128.9, 128.4,
128.1, 127.7, 127.2, 125.1, 123.9, 123.4, 122.6, 63.6, 61.6, 60.1,
21.3 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd for C25H21Cl2NO2Na+,
460.0842, found 460.0840.
(R)-3-((Z)-2-Chloro-2-(p–tolyl)vinyl)-2-((R)-2-hydroxy-1-phenyleth-
yl)-5,6-dimethoxyisoindolin-1-one (11b). White solid (238 mg,
°
(R)-6-Chloro-3-((Z)-2-chloro-2-(2-fluorophenyl)vinyl)-2-((R)-2-
hydroxy-1-phenylethyl)isoindolin-1-one (10d). Colorless oil
(241 mg, 69%); ½a�2D2 =À 47.8 (c 1.00, CHCl3); IR (film): νmax 3061,
65%), mp 108–110 C; ½a�D21 =À 57.1 (c 1.00, CHCl3); IR (film): νmax
1
3026, 2925, 1663, 1502, 1465, 1302, 1220, 1081, 757, 699 cmÀ 1; H
NMR (400 MHz, CDCl3) δ 7.44–7.39 (m, 2H), 7.34–7.28 (m, 5H), 7.20–
7.14 (m, 2H), 6.82–6.78 (m, 1H), 5.75 (d, J=9.2 Hz, 1H), 5.54 (d, J=
9.2 Hz, 1H), 4.86 (dd, J=8.0, 4.0 Hz, 1H), 4.55 (brs, 1H), 4.44 (dd, J=
12.0, 8.8 Hz, 1H), 4.15 (dd, J=11.6, 3.6 Hz, 1H), 3.95 (s, 3H), 3.88 (s,
3H), 2.37 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 170.0, 153.3,
150.3, 139.9, 138.5, 138.1, 137.8, 133.6, 129.2, 128.7, 127.9, 127.6,
126.5, 124.2, 122.8, 105.3, 104.8, 64.0, 62.0, 60.3, 56.3, 21.2 ppm;
HRMS (ESI) m/z: [M+Na]+ Calcd for C27H26ClNO4Na+, 486.1443,
found 486.1444.
1
2926, 2851, 1679, 1487, 1434, 1344, 1196, 762, 701 cmÀ 1; H NMR
(400 MHz, CDCl3) δ 7.82–7.74 (m, 1H), 7.51–7.26 (m, 9H), 7.18–7.05
(m, 2H), 5.77 (d, J=9.2 Hz, 1H), 5.62 (d, J=9.2 Hz, 1H), 4.94–4.86 (m,
1H), 4.60–4.48 (m, 1H), 4.34 (brs, 1H), 4.19–4.11 (m, 1H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 168.4, 159.3 (d, J=250.5 Hz), 141.8, 137.6,
135.2, 133.8, 132.5, 132.2, 131.2 (d, J=8.5 Hz), 130.2, 128.8, 128.3 (d,
J=6.7 Hz), 128.2, 127.8, 125.0 (d, J=11.7 Hz), 124.3, 124.0, 124.2 (d,
J=3.6 Hz), 116.2 (d, J=22.3 Hz), 63.6, 62.2, 60.3 ppm; 19F NMR
(376 MHz, CDCl3) δ À 113.1 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd
for C24H18Cl2FNO2Na+, 464.0591, found 464.0594.
(R)-3-((Z)-2-(4-Butylphenyl)-2-chlorovinyl)-2-((R)-2-hydroxy-1-phe-
nylethyl)-5,6-dimethoxyisoindolin-1-one (11c). Colorless oil
(247 mg, 62%); ½a�2D0 =À 22.4 (c 1.00, CHCl3); IR (film): νmax 2922,
(R)-6-Chloro-3-((Z)-2-chloro-2-(4-chlorophenyl)vinyl)-2-((R)-2-
hydroxy-1-phenylethyl)isoindolin-1-one (10e). Colorless oil
(264 mg, 73%); ½a�2D1 =À 55.1 (c 1.00, CHCl3); IR (film): νmax 3060,
1
2851, 1669, 1599, 1494, 1390, 1300, 1217, 769, 696 cmÀ 1; H NMR
(400 MHz, CDCl3) δ 7.48–7.42 (m, 2H), 7.35–7.27 (m, 6H), 7.20–7.16
(m, 2H), 6.82–6.78 (m, 1H), 5.77 (d, J=9.2 Hz, 1H), 5.53 (d, J=9.2 Hz,
1H), 4.87–4.76 (m, 1H), 4.63–4.37 (m, 2H), 4.17–4.10 (m, 1H), 3.96 (s,
3H), 3.89 (s, 3H), 2.60–2.61 (m, 2H), 1.62–1.56 (m, 2H), 1.37–1.32 (m,
2H), 0.94–0.90 (m, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 170.0,
153.3, 150.3, 145.0, 138.6, 138.1, 137.8, 133.7, 128.7, 128.6, 127.9,
127.6, 126.5, 124.2, 122.8, 105.3, 104.8, 64.1, 62.1, 60.4, 56.3, 35.3,
33.5, 22.3, 13.9 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd for
C30H32ClNO4Na+, 506.2096, found 506.2097.
1
2925, 1681, 1611, 1492, 1395, 1352, 1088, 826, 701 cmÀ 1; H NMR
(400 MHz, CDCl3) δ 7.80–7.74 (m, 1H), 7.47–7.42 (m, 1H), 7.40–7.42
(m, 1H), 7.40–7.37 (m, 1H), 7.37–7.32 (m, 7H), 7.32–7.25 (m, 2H), 5.72
(d, J=9.2 Hz, 1H), 5.69 (d, J=9.2 Hz, 1H), 5.05 (dd, J=8.8, 3.6 Hz,
1H), 4.61–4.47 (m, 1H), 4.21 (dd, J=12.0, 4.0 Hz, 1H), 4.13 (brs, 1H)
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 168.7, 145.3, 138.7, 137.7,
137.3, 135.8, 134.7, 130.4, 129.5, 128.8, 128.6, 128.1, 127.9, 127.7,
125.1, 123.8, 123.4, 63.1, 60.8, 59.7 ppm; HRMS (ESI) m/z: [M+Na]+
Calcd for C24H18Cl3NO2Na+, 480.0295, found 480.0298.
(R)-3-((Z)-2-Chloro-2-(2-fluorophenyl)vinyl)-2-((R)-2-hydroxy-1-
phenylethyl)-5,6-dimethoxyisoindolin-1-one (11d). Colorless oil
(280 mg, 76%); ½a�2D1 =À 57.7 (c 1.00, CHCl3); IR (film): νmax 2926,
(R)-6-Chloro-3-((Z)-2-chloro-2-(thiophen-2-yl)vinyl)-2-((R)-2-
hydroxy-1-phenylethyl)isoindolin-1-one (10f). Colorless oil
(241 mg, 71%); ½a�2D2 =À 52.7 (c 0.3, CHCl3); IR (film): νmax 3061, 2926,
1
1667, 1498, 1348, 1298, 1219, 1075, 1031, 761, 699 cmÀ 1; H NMR
2851, 1679, 1487, 1434, 1344, 1196, 762, 701 cmÀ 1
;
1H NMR
(400 MHz, CDCl3) δ 7.51–7.43 (m, 1H), 7.38–7.24 (m, 7H), 7.20–7.15
(m, 1H), 7.13–7.05 (m, 1H), 6.89–6.83 (m, 1H), 5.79 (d, J=9.2 Hz, 1H),
5.52 (d, J=9.2 Hz, 1H), 4.89–4.79 (m, 1H), 4.61 (brs, 1H), 4.52–4.39
(m, 1H), 4.20–4.14 (m, 1H), 3.95 (s, 3H), 3.92 (s, 3H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 170.1, 159.3 (d, J=250.3 Hz), 153.4, 150.4,
138.0, 137.3, 131.7, 131.1 (d, J=8.6 Hz), 130.2, 129.2 (d, J=6.6 Hz),
128.7, 128.0, 127.7, 125.2 (d, J=11.7 Hz), 124.3, 124.2 (d, J=3.5 Hz),
116.2 (d, J=22.3 Hz), 105.3, 104.8, 64.2, 62.4, 60.2, 56.4, 56.3 ppm;
19F NMR (376 MHz, CDCl3) δ À 113.6 ppm; HRMS (ESI) m/z: [M+Na]+
Calcd for C26H23ClFNO4Na+, 490.1192, found 490.1193.
(400 MHz, CDCl3) δ 7.83–7.77 (m, 1H), 7.57–7.53 (m, 1H), 7.49–7.45
(m, 1H), 7.41–7.38 (m, 1H), 7.36–7.28 (m, 6H), 7.11–7.07 (m, 1H), 5.72
(d, J=9.2 Hz, 1H), 5.65 (d, J=9.2 Hz, 1H), 4.95 (dd, J=9.2, 3.6 Hz,
1H), 4.53 (dd, J=11.6, 7.2 Hz, 1H), 4.31–4.05 (m, 2H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 168.7, 145.5, 138.7, 138.1, 137.7, 133.6,
130.5, 129.5, 128.8, 128.1, 127.7, 126.8, 125.1, 124.8, 123.5, 121.4,
63.4, 61.5, 59.8 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd for
C22H17Cl2NO2SNa+, 452.0249, found 452.0248.
(R)-6-Chloro-3-((Z)-2-chloro-2-(thiophen-3-yl)vinyl)-2-((R)-2-
hydroxy-1-phenylethyl)isoindolin-1-one (10g). Colorless oil
(153 mg, 45%); ½a�2D4 =À 22.7 (c 1.00, CHCl3); IR (film): νmax 2928,
(R)-3-((Z)-2-(3-Bromophenyl)-2-chlorovinyl)-2-((R)-2-hydroxy-1-
phenylethyl)-5,6-dimethoxyisoindolin-1-one (11e). Colorless oil
(304 mg, 73%); ½a�2D0 =À 89.0 (c 1.00, CHCl3); IR (film): νmax 2930,
1
1666, 1606, 1501, 1467, 1300, 1223, 1120, 1073, 828, 699 cmÀ 1; H
1
NMR (400 MHz, CDCl3) δ 7.82–7.77 (m, 1H), 7.56–7.51 (m, 1H), 7.48–
7.44 (m, 1H), 7.38–7.36 (m, 1H), 7.35–7.27 (m, 6H), 7.11–7.06 (m, 1H),
5.71 (d, J=9.2 Hz, 1H), 5.60 (d, J=9.2 Hz, 1H), 4.88 (dd, J=8.4,
3.2 Hz, 1H), 4.55–4.45 (m, 1H), 4.15 (dd, J =12.4, 3.6 Hz, 1H), 4.16
(brs, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 168.7, 145.5, 138.7,
138.0, 137.6, 133.8, 130.5, 129.5, 128.8, 128.2, 127.7, 126.9, 125.1
(2 C), 124.8, 123.5, 121.3, 63.6, 61.8, 59.8 ppm; HRMS (ESI) m/z: [M+
Na]+ Calcd for C22H17Cl2NO2SNa+, 452.0249, found 452.0252.
1666, 1501, 1424, 1382, 1300, 1217, 1078, 759, 700 cmÀ 1; H NMR
(400 MHz, CDCl3) δ 7.50–7.42 (m, 1H), 7.35–7.30 (m, 6H), 7.27–7.23
(m, 1H), 7.18–7.12 (m, 6H), 7.17–7.13 (m, 1H), 7.10–7.03 (m, 1H),
6.85–6.81 (m, 1H), 5.78 (d, J=9.2 Hz, 1H), 5.48 (d, J=8.8 Hz, 1H),
4.84–4.81 (m, 1H), 4.64–4.56 (m, 1H), 4.51–4.35 (m, 1H), 4.17–4.10
(m, 1H), 3.93 (s, 3H), 3.89 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
δ 170.0, 153.4, 150,5, 138.3, 137.9, 137.3, 136.5, 132.5, 130.0, 129.6,
128.8, 128.1, 127.6, 125.5, 125.2, 124.3, 122.7, 105.4, 104.8, 63.9,
61.7, 59.9, 56.4 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd for
C26H23ClBrNO4Na+, 550.0391, found 550.0394.
(R)-3-((Z)-2-Chloro-2-phenylvinyl)-2-((R)-2-hydroxy-1-phenyleth-
yl)-5,6-dimethoxyisoindolin-1-one (11a). White solid (248 mg,
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(R)-3-((Z)-2-Chloro-2-(3-methoxyphenyl)vinyl)-2-((R)-2-hydroxy-1-
phenylethyl)-5,6-dimethoxyisoindolin-1-one (11f). Colorless oil
(250 mg, 66%); ½a�2D5 =À 66.7 (c 1.00, CHCl3); IR (film): νmax 2924,
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1
2851, 1665, 1597, 1500, 1467, 1295, 1216, 777, 696 cmÀ 1; H NMR
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(m, 1H), 6.83–6.74 (m, 1H), 5.81 (d, J=9.2 Hz, 1H), 5.50 (d, J=8.8 Hz,
1H), 4.80–4.76 (m, 1H), 4.49–4.42 (m, 2H), 4.17–4.09 (m, 1H), 3.94 (s,
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170.0, 159.6, 153.4, 150.4, 138.2, 138.0, 137.7, 137.6, 129.5, 128.7,
128.0, 127.6, 124.3, 124.1, 119.0, 115.1, 112.5, 105.3, 104.9, 64.1,
62.1, 60.3, 56.4, 56.3, 55.5 ppm; HRMS (ESI) m/z: [M+Na]+ Calcd for
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Deposition Numbers 2055347 (for 9j), and 2055348 (for 9p)
contain the supplementary crystallographic data for this paper.
These data are provided free of charge by the joint Cambridge
Crystallographic Data Centre and Fachinformationszentrum Karls-
ruhe Access Structures service www.ccdc.cam.ac.uk/structures.
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We thank the National Natural Science Foundation of China
(21772027) for financial support. We also thank Dr Han-Qing
Dong (Arvinas, Inc.) for helpful suggestions.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Chiral isoindolinone scaffolds · Diastereoselectivity ·
Lewis acids · N,O-acetal · Terminal alkynes
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Manuscript received: March 24, 2021
Revised manuscript received: April 18, 2021
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