Approach to Chiral 1-Substituted Isoquinolone and 3-Substituted Isoindolin-1-one by Addition-Cyclization Process

Article abstract of DOI:10.1021/acs.joc.8b01282

An approach to access 1-substituted isoquinolones has been developed through the addition-cyclization of imines with Grignard reagents in the presence of 2,2′-dipyridyl. A number of substituted aromatic magnesium reagents were amenable to this process, and the desired products were obtained with excellent yields and outstanding diastereoselectivities (dr > 99:1). The utility of this convenient approach is demonstrated by the formal synthesis of (S)-cryptostyline II. Moreover, N-methylmorpholine (NMM) was found to be an effective additive for the formation of 3-substituted isoindolin-1-ones using one-pot addition-cyclization-deprotection of imine with Grignard reagents.

Full text of DOI:10.1021/acs.joc.8b01282

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Article
Approach to Chiral 1-Substituted Isoquinolone and 3-
Substituted Isoindolin-1-one by Addition-Cyclization Process
Wen Zhou, Yan-Xue Zhang, Xiao-Di Nie, Chang-Mei Si, Xun Sun, and Bang-Guo Wei
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01282 • Publication Date (Web): 28 Jun 2018
Downloaded from http://pubs.acs.org on July 1, 2018
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Approach to Chiral 1ꢀSubstituted Isoquinolone and 3ꢀSubstituted
Isoindolinꢀ1ꢀone by AdditionꢀCyclization Process
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Wen Zhou, YanꢀXue Zhang, XiaoꢀDi Nie, ChangꢀMei Si,*Xun Sun and BangꢀGuo Wei*
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Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826
Zhangheng Road, Shanghai, 201203, The People's Republic of China.
Abstract
An approach to access 1ꢀsubstitutedꢀisoquinolones has been developed through the
additionꢀcyclization of imines with Grignard reagents in the presence of
2,2’ꢀdipyridyl. A number of substituted aromatic magnesium reagents were amenable
to this process, and the desired products were obtained with excellent yields and
outstanding diastereoselectivities (dr>99:1). The utility of this convenient approach is
demonstrated by the formal synthesis of (S)ꢀcryptostyline II. Moreover,
Nꢀmethylmorpholine (NMM) was found to be an effective additive for the formation
of 3ꢀsubstitutedisoindolinꢀ1ꢀones using oneꢀpot additionꢀcyclizationꢀdeprotection of
imine with Grignard reagents.
Introduction
The enantioselective construction of a stereogenic center at the ɑꢀposition of
nitrogenꢀcontaining heterocycles (Nꢀheterocycles) is one of the top research topics in
synthetic heterocyclic chemistry. Many chiral pharmaceutical agents contain these
skeletons1.
Among
them,
chiral
1ꢀsubstituted
ꢀisoquinolone
1
and
3ꢀsubstitutedisoindolinꢀ1ꢀone 2 are widely served as key intermediates in the
synthesis of isoquinoline and indole alkaloids2. For instance, (S)ꢀcryptostyline I, II, III
(3ꢀ5), isolated from Cryptostylis fulva and Cryptostylis erythroglosa3a , are used as
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probes for dopamine receptor D13b. Canadine (6), a protoberberine alkaloid isolated
from Corydalis yanhusuo, can act as a calcium channel blocker4. PDꢀ172938 (7)5
shows good affinity for dopamine D4 receptor, and lennoxamine (8)6 is an alkaloid
isolated from barberries species (Figure 1).
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Figure 1. Structures of several natural products.
From the synthetic point of view, 1ꢀsubstitutedꢀisoquinolone 1 could be conveniently
converted to 1ꢀsubstitutedꢀtetrahydroisoquinoline although the latter was readily
accessible through catalytic enantioselective processes such as asymmetric
hydrogenation of amines or imines7, the copperꢀcatalyzed allylation8, asymmetric
alkynylation/lactamization cascade process9,10 and palladiumꢀcatalyzed intramolecular
allylic amination11, as well as other diastereoselective processes12. Asymmetric
approaches to isoquinolone 1 include an intramolecular Heck cyclization13,
1,3ꢀmembered ringꢀclosure of chiral hydrazones14 and reactions of chiral acyliminium
ions15, as well as a chiralꢀappendageꢀmediated carbanion method16. In spite of these
robust processes, a straightforward and high diastereoselective approach to
isoquinolone 1 is still in demand. As for 3ꢀsubstituted isoindolinꢀ1ꢀone 2, recent
efforts led to a number of powerful approaches including reduction of Nꢀimide ion17,
nucleophilic addition18, coupling of aryl boric acid with imide19 and multi component
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Mannich reaction20. Due to the potential racemization of 3ꢀsubsituted
isoindolinꢀ1ꢀones under acidic, basic or reductive conditions17a, the straightforward
and efficient approach to chiral 3ꢀaryl isoindolinꢀ1ꢀones is still quite limited.
Therefore, an efficient method to chiral 3ꢀaryl isoindolinꢀ1ꢀones under mild
racemizationꢀfree conditions is still needed.
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Nowadays, diastereoselective addition controlled by Davis and Ellman’s chiral
auxiliaries (e.g. pꢀtoluenesulfinamide and 2ꢀmethylpropaneꢀ2ꢀsulfinamide) is one of
the most versatile and practical methods to chiral amines21. In recent years, we
explored the chemistry in this field22,23, and successfully developed a oneꢀpot
intramolecular
tandem
protocol
to
access
or
transꢀ5ꢀhydroxyꢀ6ꢀsubstitutedꢀ2ꢀpiperidinones
transꢀ4ꢀhydroxyꢀ5ꢀsubstitutedꢀ2ꢀpyrrolidinones through the nucleophilic addition of
αꢀchiral aldimines with Grignard reagents22. Encouraged by our previous results (Fig.
2,
eq.
1),
we
envisioned
that
1ꢀsubstitutedꢀisoquinolone
(1)/3ꢀsubstitutedisoindolinꢀ1ꢀone (2) should be accessible via the additionꢀcyclization
process of the imine 9/10/13/15 with Grignard reagents (Fig. 2, eq. 2). In continuation
of our efforts to develop effective synthetic approaches to ɑꢀchiral substituted
nitrogenꢀcontaining heterocycles, herein we describe our exploration in this aspect to
provide 1ꢀsubstitutedꢀisoquinolone scaffold (1), 3ꢀsubstituted isoindolinꢀ1ꢀone (2) and
its application in total synthesis of (S)ꢀ(+)ꢀcryptostyline II (4).
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Figure 2. Our strategy to access 11/12/14/16.
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Results and discussions
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Our investigation started with the addition of imine 9 with phenyl magnesium
bromide. As shown in Table 1, neither desired addition nor additionꢀcyclization
product 11a was isolated under multiple conditions. The attempt to use Lewis acids,
such as AlMe3 and ZnCl224a, turned out to be fruitless (Table 1, entries 1ꢀ4). We
suspected that the high reactivity of Grignard reagent caused the messy reactions. The
complexation of Grignard reagent with a simple organic ligand (such as TMEDA,
BDMAEE, etc.)24bꢀd is one of the most effective means to lower its reactivity. Several
additives were examined and the results are summarized (Table 1, entries 5ꢀ12). First,
bis(2ꢀdimethylaminoethyl) ether (BDMAEE) was examined based on literature,
unfortunately no conversion of imine 9 was observed (Table 1, entry 5). Considering
the additional complexation of oxygen in BDMAEE, tetramethylethylenediamine
(TMEDA) was then investigated. To our delight, the desired 11a was generated in
45% yield with high diastereoselectivity (dr>99:1) (Table 1, entries 6ꢀ7). The reason
of low yield was probably that the complexation ability of BDMAEE or TMEDA is
too strong regarding the nucleophilic attack to imine double bond. To verify this
hypothesis, other additives with weak complexing ability like Nꢀmethylmorpholine
(NMM)24e, PPh3 and triethylamine (TEA) were examined (Table 1, entries 8ꢀ10).
When TEA was used, the desired additionꢀcyclization product 11a was produced in
65% yield with high diastereoselectivity (dr>99:1) (Table 1, entry 10). Notably,
2,2’ꢀdipyridyl could afford the desired 11a in 77% yield with high diastereoselectivity
(dr>99:1) (Table 1, entry 11). When oꢀPhenanthroline was used, the desired product
11a was given in 41% yield (dr>99:1) (Table 1, entry 12), suggesting that
oꢀphenanthroline may complex with PhMgBr more tightly than 2,2’ꢀdipyridyl.
Table 1. Optimization of the additionꢀcyclization.
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O
O
N
tBu
Additive
O
S
PhMgBr
N
tBu
O
7
S
8
9
9
O
Proposed coordination mode:
11a
10
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O
O
O
Mg
N
N
N
N
NMM
Mg
N
Ph
BDMAEE
Br
Br
Ph
N
N
N
N
Mg
Br
Mg
Br
TMEDA
N
Mg
Br
Ph
Ph
Ph
o-Phenanthroline
2,2'-Dipyridyl
Entrya
additive
/
Solvent
THF
T/oC
Y%b
drc
1
2
ꢀ15 complex
ꢀ
AlMe3
THF
ꢀ78
ꢀ78
NR
NR
ꢀ
3
ZnCl2
THF
ꢀ
4
/
THF/DCM ꢀ78 complex
ꢀ
5
BDMAEE
TMEDA
TMEDA
NMM
THF
THF
ꢀ15
ꢀ15
NR
32
45
53
40
65
77
41
ꢀ
6
99:1
99:1
99:1
99:1
99:1
99:1
99:1
7
THF/DCM ꢀ15
THF/DCM ꢀ15
THF/DCM ꢀ15
THF/DCM ꢀ15
THF/DCM ꢀ15
THF/DCM ꢀ15
8
9
PPh3
10
11
12
TEA
2,2’ꢀDipyridyl
oꢀPhenanthroline
a
The reactions were performed with aldimine
9
(1.00 mmol), additive (6.00 mmol) (for
ꢀphenanthroline, 3.00 mmol
bidentate additives, BDMAEE, TMEDA, 2,2’ꢀdipyridyl and
o
was used), PhMgBr (3.0 mL, 1.0 M in THF) in dry solvent (6 mL) for 1 h. b Isolated yield.
c dr was determined by 1H NMR.
Next, we turned our attention to investigate the scope and limitation of this
additionꢀcyclization process for substituted imines 9/13 and various Grignard reagents.
Different substituted aryl Grignard reagents were surveyed under the above optimal
conditions, as summarized in Scheme 1. Orthoꢀ, paraꢀ and metaꢀsubstituted aryl
Grignard reagents all proved to be suitable substrates, giving the desired products
with high diastereoselectivities and in good yields (11bꢀl and 14bꢀe). Moreover, αꢀ
and βꢀnaphthyl Grignard reagents could give the desired products 11mꢀn and 14f in
moderate yields and with excellent diastereoselectivities (dr>99:1). On the other hand,
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the reactions with alkyl Grignard reagents were generally poor, affording the desired
products 11oꢀp in moderate yields and with low diastereoselectivities. We also
explored the cyclic or hindered chain Grignard reagents (cyclopentyl, isopropyl,
tertꢀbutyl, ect.) none of them could generate the desired product.
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Scheme 1. Reactions with different Grignard reagents.
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R1
R2
O
R1
R2
OMe
2,2'-Dipyridyl
RMgBr
N
tBu
O
S
N
tBu
R
O
S
11 (R1=R2=H)
9 (R1=R2=H)
O
14(R1=R2=OMe)
13 (R1=R2=OMe)
10
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O
O
N
tBu
N
tBu
S
S
O
O
F
11g, 84%, dr>99:1
R'
11a, R'=H, 77%, dr>99:1
11b, R'=Me, 74%, dr>99:1
11c, R'=OMe, 70%, dr>99:1
11d, R'=Ph, 81%, dr>99:1
11e, R'=Bu, 83%, dr>99:1
O
N
tBu
S
O
11f, R'=F, 77%, dr>99:1
R'
11h, R'=OMe, 65%, dr>99:1
11i, R'=CF3, 72%, dr>99:1
11j, R'=CH3, 69%, dr>99:1
O
O
N
tBu
S
O
N
tBu
S
O
11k, 79%, dr>99:1
MeO
tBu
O
N
tBu
R1
O
S
O
N
R2
S
11l, 66%, dr>99:1
R'
O
11o, R'=Vinyl, 50%, dr=80:20
11p, R'=Ethyl, 41%, dr=77:23
MeO
O
N
tBu
11n, R1=R2=H, 72%, dr>99:1
14f, R1=R2=OMe, 66%, dr>99:1
MeO
S
O
O
R'2
N
tBu
R'1
S
14a, R'1=R'2=H, 52%, dr>99:1
O
14b, R'1=Ph, R'2=H, 76%, dr>99:1
14c, R'1=H, R'2=F, 81%, dr>99:1
14d, R'1=H, R'2=CF3, 65%, dr>99:1
14e, R'1=R'2=OMe, 52%, dr>99:1
11m, 70%, dr>99:1
a
The reactions were performed with aldimine
9 (1.00 mmol), 2,2’ꢀdipyridyl (3.00 mmol),
o
b
RMgBr (3.0 mL, 1.0 M in THF) in dry DCM (6 mL) at ꢀ15 C for 1 h to give 11
.
The
reactions were performed with aldimine 13 (1.00 mmol), 2,2’ꢀdipyridyl (3.00 mmol),
RMgBr (3.0 mL, 1.0 M in THF) in dry DCM (6 mL) at ꢀ50 C for 1 h to give 14. c Isolated
o
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yield. d dr was determined by 1H NMR.
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5
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8
[1,3]Dioxolo[4,5ꢀg]isoquinolines widely exist in nature. We explored the
reaction of substrate 15 with Grignard reagents, as summarized in Scheme 2.
Phenyl, 3ꢀfluorophenyl, 3ꢀtrifluoromethylphenyl, 4ꢀphenylphenyl and
9
10
11
12
13
14
15
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β
ꢀnaphthyl Grignard reagents all led to the desired products with high
diastereoselectivities (dr>99:1) and in good yields (16aꢀe).
Scheme 2. The additionꢀcyclization of other substrates.
OMe
O
O
O
O
O
2,2'-Dipyridyl
O
N
tBu
S
RMgBr
N
tBu
R
O
S
O
16
15
O
O
O
O
N
tBu
N
tBu
O
O
S
S
O
O
F
16a, 69%, dr>99:1
16b, 59%, dr>99:1
O
O
O
O
O
O
tBu
N
tBu
N
S
S
O
O
F3C
Ph
16d, 92%, dr>99:1
16c, 63%, dr>99:1
O
O
N
tBu
O
S
O
16e, 72%, dr>99:1
a The reactions were performed with aldimine 15 (1.00 mmol), 2,2’ꢀdipyridyl (3.00 mmol),
RMgBr (3.0 mL, 1.0 M in THF) in dry DCM (6 mL) at ꢀ15 C for 1 h. b Isolated yield. c dr
o
was determined by 1H NMR.
The relative stereochemistry of the products 11aꢀp, 14aꢀf and 16aꢀe were
unambiguously assigned as transꢀform by Xꢀray crystallographical analysis of
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compounds 11g and 16d (see the Supporting Information).
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The removal of chiral auxiliary was straightforward and with high yield. For
example, the treatment of chiral 1ꢀsubstituted isoquinolone 14e with HCl/MeOH
generated in situ from oxalyl chloride [(COCl)2] and methanol produced the
known lactam 17 in 91% yield, which could be readily converted to
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(
S
)ꢀ(+)ꢀcryptostyline II (
4
)13a(Scheme 3).
Scheme 3. The application in formal synthesis of (
S
)ꢀ(+)ꢀcryptostyline II.
Next, we turned our attention to investigate the tandem process of
αꢀchiral
aldimine 10 with Grignard reagents. Due to the easy racemization of the
3ꢀcarbonꢀsubsituted isoindolinꢀ1ꢀones 12 under acidic, basic or reductive
conditions, straightforward and efficient approach is still quite limited17b. Very
recently, an interesting preparation of chiral 3ꢀcarbonꢀsubsituted
isoindolinꢀ1ꢀones motivated us to expand our chemistry to the imine substrate
10
with
Grignard
reagents18h.
Although
the
desired
additionꢀcyclizationꢀdeprotection product 12a was generated in 92% yield
when the imine 10 was treated with 4ꢀmethoxyphenyl magnesium bromide, the
enantioselectivity was relatively low compared with the results for substrates
9/13/15. Moreover, almost none of the results are repeatable for this process (Table
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2, entry 1). The addition of other simple organic ligands (such as TMEDA,
BDMAEE et al.) failed to improve the enantioselectivity of 12a (Table 2,
entries 2ꢀ4). When NMM was used, the enantioselectivity could reach to 88%
(Table 2, entries 5ꢀ6).
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Table 2. Optimization of the additionꢀdeprotectionꢀcyclization.
O
O
OMe
4-MeOPhMgBr
Additive
NH
N
tBu
S
O
OMe
Y%b ee%c
10
12a
Entrya
Additive
T/oC
20
solvent
DCM
1
2
3
4
5
6
/
92
ꢀꢀ
74
67
ꢀꢀ
2,2’ꢀDipyridyl ꢀ15 THF/DCM 85
TMEDA
BDMAEE
NMM
ꢀ15
ꢀ15
ꢀ15
ꢀ78
THF
THF
THF
THF
86
NR
87
88d
NMM
60
77
a
The reactions were performed with aldimine 10 (0.75 mmol), additive (2,2’ꢀdipyridyl,
TMEDA and BDMAEE for 2.25 mmol; NMM for 4.50 mmol), 4ꢀmethoxyphenyl
b
magnesium bromide (2.3 mL, 1.0 M in THF) in dry solvent (3 mL) for 2.5 h. Isolated
c
d
yield. ee was determined by HPLC. When the 12a was recrystallized in EA/PE, the
enantioselectivity of new crystal could reach to 97.5% ee
.
With NMM as the organic base ligand, various Grignard reagents were also
examined and the results are summarized in Scheme 4. In general, most substituted
aromatic Grignard reagents could react smoothly to afford 3ꢀaryl isoindolinꢀ1ꢀones in
excellent yields and with moderate to good enantioselectivities (12aꢀg and 12iꢀk),
while several orthoꢀ or metaꢀsubstituted aromatic Grignard reagents led to slightly
lower enantioselectivities for the desired products (12h and 12l). A few bicyclic
aromatic reagents, including αꢀ and βꢀnaphthyl Grignard reagents, also afforded the
desired tandem products (12mꢀn) in excellent yields and with good
enantioselectivities.
Scheme 4. The additionꢀcyclizationꢀdeprotection of substrate 10.
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a
The reactions were performed with aldimine 10 (0.75 mmol), NMM (4.50 mmol),
Grignard reagents (2.3 mL, 1.0 M in THF) in dry THF (3 mL) at ꢀ15 °C for 2.5 h. b Isolated
yield. c ee was determined by HPLC.
Conclusion
In summary, we established a convenient and oneꢀpot method for highly
diastereoselective synthesis of 1ꢀsubstituted isoquinolones 11aꢀn, 14aꢀg and 16aꢀe
through the reactions of 9/13/15 with Grignard reagents. It is worth mentioning that
2,2’ꢀdipyridyl was found as an effective additive to improve the diastereoselectivity
(dr>99:1) of 11aꢀn, 14aꢀg and 16aꢀe. This convenient approach was utilized to
formally synthesize the (S)ꢀcryptostyline II (4). Moreover, for the formation of
3ꢀsubstituted isoindolinꢀ1ꢀones 12aꢀn by oneꢀpot additionꢀcyclizationꢀdeprotection of
imine 10 with Grignard reagents, 4ꢀmethylmorpholine (NMM) was found to be an
effective additive. Interestingly, the chiral auxiliary was simultaneously removed
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under the reaction conditions, and the desired 3ꢀsubstituted isoindolinꢀ1ꢀones 12a−n
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were obtained in high yields and with good enantioselectivities.
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Experimental Section
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General Considerations THF was distilled from sodium/benzophenone. Reactions
were monitored by thin layer chromatography (TLC) on glass plates coated with silica
gel with fluorescent indicator. Flash chromatography was performed on silica gel
(300−400) with PE/EA as eluent. Optical rotations were measured on a polarimeter
with a sodium lamp. HRMS were measured on LTQꢀOrbit. IR spectra were recorded
using film on a Fourier Transform Infrared Spectrometer. NMR spectra were recorded
at 400 MHz, and chemical shifts are reported in δ (ppm) referenced to an internal
TMS standard for 1H NMR and CDCl3 (77.16 ppm) for 13C NMR.
Methyl (R,E)ꢀ2ꢀ(2ꢀ(((tertꢀbutylsulfinyl)imino)methyl)phenyl)acetate 9
To a solution of oꢀTolylacetic acid (20.00 g, 133.17 mmol), CH3I (24.9 mL, 399.52
mmol), NaHCO3 (22.37 g, 266.35 mmol) were stirred in DMF (200 mL) at room
temperature for 12h. Then the mixture was quenched with water as well as extracted
with EA for four times. The combined organic layers were washed with water and
brine. Dried, filtrated and concentrated, the residue was dissolved in CH3CN (200 mL)
and treated with NBS (26.07 g, 146.49 mmol) at 80oC for 2h. Then the mixture was
concentrated and purified by flash chromatography on silica gel (PE/EA=20/1) to give
brominated compound (30.43 g, 94%). The brominated compound (30.43 g, 125.17
mmol) was dissolved in CHCl3 (200 mL) and treated with Bis(tetrabutylammonium)
dichromate (TBADC) (105.29 g, 150.21 mmol) at 70oC for 1h. Then the mixture was
concentrated. The residue was quenched with a saturated aqueous solution of
NaHCO3 and extracted with EtOAc (200 mL × 3). The combined organic layers were
washed with brine. Dried, filtrated and concentrated, the residue was purified by flash
chromatography on silica gel (PE/EA=9/1) to give aldehyde (17.40 g, 78%), which
was dissolved in DCM (120 mL). Then (R)ꢀ2ꢀ methylꢀ2ꢀpropanesulfinamide (11.82 g,
97.65 mmol), cupric sulphate anhydrous (31.17 g, 195.30 mmol) and PPTS (2.46 g,
9.77 mmol) were added in one portion and the mixture was stirred for 24 h. The
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resulting mixture was filtrated and the filtrate was concentrated to give the crude
product, which was purified by flash chromatography on silica gel (PE/EA=4/1) to
give compound 9 (24.73 g, 90%) as a colorless oil. [α]D23= ꢀ95.5 (c 1.00, CHCl3); IR
(film) νmax 2954, 1739, 1605, 1569, 1435, 1364, 1341, 1314, 1164, 1083, 919, 761
10
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1
cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.88ꢀ7.82 (m, 1H), 7.50ꢀ7.40 (m,
13
2H), 7.33ꢀ7.29 (m, 1H), 4.12ꢀ4.00 (m, 2H), 3.66 (s, 3H), 1.26 (s, 9H) ppm; C NMR
(100 MHz, CDCl3) δ 171.4, 162.8, 135.0, 132.5, 132.5, 132.2, 132.1, 128.0, 57.5, 52.2,
39.5, 22.5 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for C14H20NO3S: 282.1158,
found: 282.1159.
Methyl (R,E)ꢀ2ꢀ(((tertꢀbutylsulfinyl)imino)methyl)benzoate 10
To a solution of 2ꢀformylbenzoic acid (10.00 g, 66.61 mmol), CH3I (12.4 mL, 199.83
mmol), NaHCO3 (11.19 g, 133.22 mmol) were stirred in DMF (100 mL) at room
temperature for 12h. Then the mixture was quenched with water as well as extracted
with EA for four times. The combined organic layers were washed with water and
brine. Dried, filtrated and concentrated, the residue was dissolved in DCM (260 mL).
Then (R)ꢀ2ꢀ methylꢀ2ꢀpropanesulfinamide (8.07 g, 66.61 mmol), cupric sulphate
anhydrous (21.26 g, 133.22 mmol) and PPTS (837 mg, 3.33 mmol) were added in one
portion and the mixture was stirred for 24 h. The resulting mixture was filtrated and
the filtrate was concentrated to give the crude product, which was purified by flash
chromatography on silica gel (PE/EA=4/1) to give compound 10 (16.91 g, 95%) as a
colorless oil. [α]D22= ꢀ197.9 (c 1.00, CHCl3); IR (film) νmax 2980, 2954, 2924, 2863,
1721, 1606, 1566, 1434, 1364, 1288, 1265, 1132, 1084, 825, 764 cmꢀ1; 1H NMR (400
MHz, CDCl3) δ 9.22 (s, 1H), 8.04ꢀ8.01 (m, 1H), 7.97ꢀ7.94 (m, 1H), 7.64ꢀ7.59 (m, 1H),
7.58ꢀ7.53 (m, 1H), 3.95 (s, 3H), 1.29 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ
167.1, 162.7, 134.6, 132.2, 131.4, 131.4, 130.6, 129.0, 58.0, 52.7, 22.8 ppm; HRMS
(ESIꢀOrbitrap) m/z: [M+H]+ calcd for C13H18NO3S: 268.1002, found: 268.0996.
Methyl (R,E)ꢀ2ꢀ(2ꢀ(((tertꢀbutylsulfinyl)imino)methyl)ꢀ4,5ꢀdimethoxyphenyl)acetate
13
To a solution of 3,4ꢀdimethoxyphenylacetic acid (25.00 g, 127.42 mmol) was stirred
in AcOH (65 mL) at 80oC. Then concentrated hydrochloric acid (20 mL), HCHO (20
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mL) were added and the mixture was stirred for 2 h. The mixture was concentrated
and diluted with DCM. The organic layer was washed with a saturated aqueous
solution of NaHCO3 and brine. Dried, filtrated and concentrated, the residue was
dissolved in toluene (200 mL). Then KOH (28.01 g, 509.68 mmol), BnBr (37.8 mL,
318.55 mmol) were added in one portion and the mixture was stirred at 120 oC for 24
h. The resulting mixture was allowed to room temperature, diluted with water and
extracted with EtOAc (200 mL × 3). The combined organic layers were washed with
brine. Dried, filtrated and concentrated, the residue was dissolved in DMF (200 mL).
Then CH3I (23.8 mL, 382.26 mmol), NaHCO3 (21.41 g, 254.84 mmol) were added in
one portion and the mixture was stirred at room temperature for 12 h. The mixture
was quenched with water as well as extracted with EtOAc (200 mL × 4). The
combined organic layers were washed with water and brine. Dried, filtrated and
concentrated, the residue was purified by flash chromatography on silica gel
(PE/EA=5/1) to give ester (32.41 g, 3 steps for 77%) as a yellow oil. IR (film) νmax
2949, 2847, 2831, 1737, 1609, 1520, 1454, 1281, 1218, 1160, 1108, 936, 919, 752
10
11
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1
cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.37ꢀ7.34 (m, 4H), 7.32ꢀ7.28 (m, 1H), 6.87 (s,
1H), 6.77 (s, 1H), 4.52 (s, 4H), 3.88 (s, 3H), 3.87 (s, 3H), 3.65 (s, 2H), 3.61 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 172.3, 148.7, 148.0, 138.2, 128.9, 128.5, 128.1,
127.8, 125.7, 114.1, 113.1, 72.3, 70.4, 56.1, 56.1, 52.1, 37.8 ppm; HRMS
(ESIꢀOrbitrap) m/z: [M+H]+ calcd for C19H23O5: 331.1540, found: 331.1540. The
ester (20.00 g, 60.54 mmol), 10% Pd/C (2.00 g) and 20% Pd(OH)2/C (2.00 g) were
stirred in MeOH (300 mL) under a H2 atmosphere for 8 h. The mixture was filtered
and concentrated. The residue was dissolved in DCM (300 mL). Then DMP (30.81 g,
72.65 mmol) was added and the mixture was stirred at room temperature for 30 min.
Then the mixture was quenched with a solution of NaHCO3 and Na2S2O3 as well as
extracted with DCM (200 mL × 3). The combined organic layers were washed with
brine and dried over MgSO4. The resulting mixture was filtrated and concentrated to
give crude aldehyde, which was dissolved in DCM (300 mL). Then (R)ꢀ2ꢀ
methylꢀ2ꢀpropanesulfinamide (7.33 g, 60.54 mmol), cupric sulphate anhydrous (19.32
g, 121.08 mmol) and PPTS (0.76 g, 3.03 mmol) were added in one portion and the
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mixture was stirred for 24 h. The resulting mixture was filtrated and the filtrate was
concentrated to give the crude product, which was purified by flash chromatography
on silica gel (PE/EA=2/1) to give 13 (16.74 g, 81%) as a yellow oil. [α]D23= ꢀ31.2 (c
1.00, CHCl3); IR (film) νmax 2957, 2924, 2867, 1738, 1586, 1564, 1517, 1463, 1320,
1270, 1165, 1126, 1078, 1011, 810, 763 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.65 (s,
1H), 7.42 (s, 1H), 6.78 (s, 1H), 4.01ꢀ3.97 (m, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 3.67 (s,
3H), 1.25 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.6, 161.2, 152.1, 148.4,
129.3, 125.3, 114.3, 113.5, 57.5, 56.2, 52.2, 38.6, 24.3, 22.5 ppm; HRMS
(ESIꢀOrbitrap) m/z: [M+H]+ calcd for C16H24NO5S: 342.1370, found: 342.1370.
Methyl(R,E)ꢀ2ꢀ(6ꢀ(((tertꢀbutylsulfinyl)imino)methyl)benzo[d][1,3]dioxolꢀ5ꢀyl)acetate
15
10
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To a solution of 2ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)acetic acid (20.00 g, 111.01 mmol) was
stirred in AcOH (64 mL) at 80oC. Then concentrated hydrochloric acid (20 mL),
HCHO (20 mL) were added and the mixture was stirred for 2 h. The mixture was
concentrated and diluted with DCM. The organic layer was washed with a saturated
aqueous solution of NaHCO3 and brine. Dried, filtrated and concentrated, the residue
was dissolved in HBr/CH3OH (50 mL/200 mL). The mixture was stirred at 90oC for 2
h and concentrated. The residue was dissolved in CHCl3 (200 mL) and treated with
TBADC (77.81 g, 111.01 mmol) at 70oC for 1h. Then the mixture was concentrated
and quenched with a saturated aqueous solution of NaHCO3 as well as extracted with
EtOAc (200 mL × 3). The combined organic layers were washed with brine. Dried,
filtrated and concentrated, the residue was purified by flash chromatography on silica
gel (PE/EA=4/1) to give aldehyde (18.50 g, 75%), which was dissolved in DCM (120
mL). Then (R)ꢀ2ꢀmethylꢀ2ꢀpropanesulfinamide (10.08 g, 83.26 mmol), cupric
sulphate anhydrous (26.58 g, 166.52 mmol) and PPTS (2.09 g, 8.33 mmol) were
added in one portion and the mixture was stirred for 24 h. The resulting mixture was
filtrated and the filtrate was concentrated to give the crude product, which was
purified by flash chromatography on silica gel (PE/EA=2/1) to give compound 15
(25.47 g, 94%) as a yellow oil. [α]D23= ꢀ58.4 (c 1.00, CHCl3); IR (film) νmax 2980,
2953, 2923, 2865, 1739, 1621, 1579, 1507, 1484, 1434, 1384, 1338, 1268, 1197, 1158,
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1081, 1036, 920, 804, 771, 745 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.41
(s, 1H), 6.77 (s, 1H), 6.05ꢀ6.03 (m, 2H), 3.93 (s, 2H), 3.67 (s, 3H), 1.24 (s, 9H) ppm;
13C NMR (100 MHz, CDCl3) δ 171.3, 160.5, 151.0, 147.7, 131.2, 127.0, 111.6, 109.7,
102.1, 57.6, 52.3, 38.6, 22.6 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for
C15H20NO5S: 326.1057, found: 326.1060.
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General procedure for synthesis of 11, 14 and 16: To a compound 9, 13 or 15 (1.0
mmol) in anhydrous DCM (6 mL) was treated with a solution of Grignard reagents
(3.0 mL, 1 M in THF) and 2,2’ꢀdipyridyl (469 mg, 3.0 mmol) at ꢀ15 oC for 1h (ꢀ50oC
for 13). The mixture was quenched with a saturated NH4Cl aqueous solution and
extracted with EtOAc (30 mL × 3) and the combined organic layers were washed with
brine. Dried, filtered and concentrated, the residue was purified by flash
chromatography on silica gel to give 11 (PE/EA=4/1), 14 (PE/EA=2/1) or 16
(PE/EA=4/1).
(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ1ꢀphenylꢀ1,4ꢀdihydroisoquinolinꢀ3(2H)ꢀone (11a)
o
White solid (252 mg, 77%), m.p. 166ꢀ167 C. [α]D25= +132.1 (c 1.00, CHCl3); IR
(film) νmax 3029, 2965, 2925, 2849, 1677, 1493, 1457, 1382, 1249, 1179, 1106, 1084,
1
909, 830, 750 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.53ꢀ7.49 (m, 1H), 7.40ꢀ7.36 (m,
2H), 7.34ꢀ7.28 (m, 2H), 7.27ꢀ7.18 (m, 3H), 7.12ꢀ7.08 (m, 1H), 6.19 (s, 1H), 3.90 (d, J
= 18.8 Hz, 1H), 3.68 (d, J = 18.8 Hz, 1H), 1.15 (s, 9H) ppm; 13C NMR (100 MHz,
CDCl3) δ 174.4, 140.3, 137.7, 130.5, 129.0, 127.9, 127.8, 127.6, 126.4, 126.1, 60.4,
53.5, 39.7, 22.8 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for C19H22NO2S:
328.1366, found: 328.1367.
(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ1ꢀ(pꢀtolyl)ꢀ1,4ꢀdihydroisoquinolinꢀ3(2H)ꢀone (11b)
o
White solid (253 mg, 74%), m.p. 148ꢀ150 C. [α]D25= +116.5 (c 1.00, CHCl3); IR
(film) νmax 3008, 2967, 2925, 2861, 1676, 1512, 1458, 1381, 1250, 1179, 1109, 1084,
1
840, 746 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.52ꢀ7.47 (m, 1H), 7.28ꢀ7.23 (m, 3H),
7.22ꢀ7.17 (m, 1H), 7.14ꢀ7.08 (m, 3H), 6.15 (s, 1H), 3.90 (d, J = 18.4 Hz, 1H), 3.67 (d,
J = 18.8 Hz, 1H), 2.29 (s, 3H) 1.15 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 174.4,
138.0, 137.4, 137.3, 130.4, 129.7, 127.8, 127.8, 127.6, 126.3, 126.0, 60.4, 53.3, 39.7,
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22.9, 21.1 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for C20H24NO2S: 342.1522,
found: 342.1520.
6
(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ1,4ꢀdihydroisoquinolinꢀ3(2H)ꢀone
(11c)
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Colorless oil (250 mg, 70%). [α]D25= +116.7 (c 1.00, CHCl3); IR (film) νmax 2961,
2924, 2853, 1676, 1609, 1511, 1458, 1382, 1303, 1250, 1177, 1109, 1083, 1032, 842,
1
772, 745 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.49ꢀ7.44 (m, 1H), 7.31ꢀ7.17 (m, 4H),
7.12ꢀ7.08 (m, 1H), 6.87ꢀ6.81 (m, 2H), 6.14 (s, 1H), 3.90 (d, J = 18.8 Hz, 1H), 3.75 (s,
3H), 3.67 (d, J = 18.4 Hz, 1H), 1.16 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ
174.2, 158.9, 137.9, 132.4, 130.2, 127.7, 127.7, 127.5, 125.9, 114.3, 60.3, 55.3, 53.0,
39.6, 22.8 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for C20H24NO3S: 358.1471,
found: 358.1472.
(S)ꢀ1ꢀ([1,1'ꢀBiphenyl]ꢀ4ꢀyl)ꢀ2ꢀ((R)ꢀtertꢀbutylsulfinyl)ꢀ1,4ꢀdihydroisoquinolinꢀ3(2H)ꢀo
ne (11d)
o
White solid (327 mg, 81%), m.p. 151ꢀ153 C. [α]D26= +143.1 (c 1.00, CHCl3); IR
(film) νmax 2982, 2965, 2924, 1676, 1486, 1384, 1249, 1108, 1084, 912, 847, 756 cmꢀ1;
1H NMR (400 MHz, CDCl3) δ 7.57ꢀ7.51 (m, 5H), 7.46ꢀ7.39 (m, 4H), 7.36ꢀ7.26 (m,
2H), 7.25ꢀ7.20 (m, 1H), 7.14ꢀ7.10 (m, 1H), 6.24 (s, 1H), 3.94 (d, J = 18.8 Hz, 1H),
3.70 (d, J = 18.4 Hz, 1H), 1.18 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 174.5,
140.5, 140.2, 139.1, 137.7, 130.5, 129.0, 128.0, 127.9, 127.7, 127.6, 127.1, 126.8,
126.1, 60.4, 53.3, 39.8, 22.9 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for
C25H26NO2S: 404.1679, found: 404.1677.
(S)ꢀ1ꢀ(4ꢀbutylphenyl)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ1,4ꢀdihydroisoquinolinꢀ3(2H)ꢀone
(11e)
Colorless oil (318 mg, 83%). [α]D25= +55.1 (c 1.00, CHCl3); IR (film) νmax 2959, 2929,
2873, 2859, 1731, 1680, 1459, 1381, 1272, 1116, 1086, 843, 746 cmꢀ1; 1H NMR (400
MHz, CDCl3) δ 7.51ꢀ7.47 (m, 1H), 7.28ꢀ7.23 (m, 3H), 7.22ꢀ7.17 (m, 1H), 7.13ꢀ7.07
(m, 3H), 6.16 (s, 1H), 3.90 (d, J = 18.4 Hz, 1H), 3.66 (d, J = 18.8 Hz, 1H), 2.57ꢀ2.51
(m, 2H), 1.58ꢀ1.49 (m, 2H), 1.36ꢀ1.27 (m, 2H), 1.15 (s, 9H), 0.92ꢀ0.86 (m, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 174.4, 142.3, 137.9, 137.4, 130.5, 128.9, 127.8, 127.8,
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127.5, 126.2, 126.1, 60.4, 53.4, 39.7, 35.2, 33.5, 22.8, 22.4, 14.0 ppm; HRMS
(ESIꢀOrbitrap) m/z: [M+H]+ calcd for C23H30NO2S: 384.1992, found: 384.1993.
(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ1ꢀ(4ꢀfluorophenyl)ꢀ1,4ꢀdihydroisoquinolinꢀ3(2H)ꢀone
(11f)
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Colorless oil (266 mg, 77%). [α]D25= +119.0 (c 1.00, CHCl3); IR (film) νmax 2961,
2926, 2865, 1678, 1508, 1380, 1228, 1160, 1099, 1083, 846, 747 cmꢀ1; 1H NMR (400
MHz, CDCl3) δ 7.49ꢀ7.45 (m, 1H), 7.38ꢀ7.32 (m, 2H), 7.30ꢀ7.20 (m, 2H), 7.14ꢀ7.10
(m, 1H), 7.05ꢀ6.97 (m, 2H), 6.17 (s, 1H), 3.87 (d, J = 18.8 Hz, 1H), 3.69 (d, J = 18.4
Hz, 1H), 1.15 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 174.1, 162.0 (d, J = 245.7
Hz), 137.4, 136.3 (d, J = 2.8 Hz), 130.3, 128.1, 128.0, 127.9, 127.7, 126.1, 115.9 (d, J
= 21.5 Hz), 60.4, 52.9, 39.6, 22.9 ppm; 19F NMR (376 MHz, CDCl3) δ ꢀ114.5 ppm;
HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for C19H21FNO2S: 346.1272, found:
346.1270.
(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ1ꢀ(3ꢀfluorophenyl)ꢀ1,4ꢀdihydroisoquinolinꢀ3(2H)ꢀone
(11g)
Colorless oil (290 mg, 84%). [α]D25= +119.5 (c 0.20, CHCl3); IR (film) νmax 2959,
2921, 2851, 1680, 1590, 1488, 1380, 1249, 1116, 1085, 852, 771, 746 cmꢀ1; 1H NMR
(400 MHz, CDCl3) δ 7.52ꢀ7.46 (m, 1H), 7.33ꢀ7.21 (m, 3H), 7.20ꢀ7.16 (m, 1H),
7.14ꢀ7.10 (m, 1H), 7.10ꢀ7.05 (m, 1H), 6.96ꢀ6.89 (m, 1H), 6.17 (s, 1H), 3.87 (d, J =
18.8 Hz, 1H), 3.68 (d, J = 18.8 Hz, 1H), 1.16 (s, 9H) ppm; 13C NMR (100 MHz,
CDCl3) δ 174.2, 163.0 (d, J = 246.3 Hz), 143.0 (d, J = 6.3 Hz), 137.1, 130.7 (d, J =
8.2 Hz), 130.5, 128.2, 127.9, 127.7, 126.2, 122.0 (d, J = 1.9 Hz), 114.7 (d, J = 21.0
Hz), 113.7 (d, J = 22.4 Hz), 60.5, 53.1,, 39.6, 22.8 ppm; 19F NMR (376 MHz, CDCl3)
δ ꢀ111.1 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for C19H21FNO2S: 346.1272,
found: 346.1270.
(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ1ꢀ(3ꢀmethoxyphenyl)ꢀ1,4ꢀdihydroisoquinolinꢀ3(2H)ꢀone
(11h)
o
White solid (232 mg, 65%), m.p. 100ꢀ102 C. [α]D25= +117.1 (c 1.00, CHCl3); IR
(film) νmax 2961, 2925, 2855, 1678, 1604, 1490, 1458, 1380, 1305, 1255, 1152, 1084,
1
850, 743 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.52ꢀ7.47 (m, 1H), 7.29ꢀ7.18 (m, 3H),
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7.12ꢀ7.07 (m, 1H), 6.98ꢀ6.94 (m, 1H), 6.92ꢀ6.89 (m, 1H), 6.78ꢀ6.72 (m, 1H), 6.14 (s,
1H), 3.92 (d, J = 18.4 Hz, 1H), 3.76 (s, 3H), 3.66 (d, J = 18.8 Hz, 1H), 1.17 (s, 9H)
ppm; 13C NMR (100 MHz, CDCl3) δ 174.3, 160.0, 141.9, 137.6, 130.0, 127.9, 127.8,
127.6, 126.2, 118.6, 112.8, 112.4, 60.4, 55.3, 53.4, 39.7, 22.8 ppm; HRMS
(ESIꢀOrbitrap) m/z: [M+H]+ calcd for C20H24NO3S: 358.1471, found: 358.1475.
(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ1ꢀ(3ꢀ(trifluoromethyl)phenyl)ꢀ1,4ꢀdihydroisoquinolinꢀ3(
2H)ꢀone (11i)
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Colorless oil (285 mg, 72%). [α]D26= +95.8 (c 1.00, CHCl3); IR (film) νmax 2969, 2928,
1677, 1492, 1458, 1382, 1330, 1264, 1167, 1124, 1075, 890, 846, 748 cmꢀ1; 1H NMR
(400 MHz, CDCl3) δ 7.65ꢀ7.62 (m, 1H), 7.60ꢀ7.56 (m, 1H), 7.53ꢀ7.44 (m, 3H),
7.33ꢀ7.23 (m, 2H), 7.16ꢀ7.13 (m, 1H), 6.24 (s, 1H), 3.84 (d, J = 18.4 Hz, 1H), 3.73 (d,
J = 18.8 Hz, 1H), 1.15 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 174.3, 141.4,
136.8, 131.4 (d, J = 32.4 Hz), 130.3, 129.9, 129.7, 128.4, 128.1, 127.9, 126.2, 124.6
(d, J = 3.6 Hz), 123.8 (d, J = 271.0 Hz), 123.1 (d, J = 3.7 Hz), 60.7, 53.2, 39.6, 22.8
ppm; 19F NMR (376 MHz, CDCl3) δ ꢀ62.8 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+
calcd for C20H21F3NO2S: 396.1240, found: 396.1238.
(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ1ꢀ(mꢀtolyl)ꢀ1,4ꢀdihydroisoquinolinꢀ3(2H)ꢀone (11j)
o
White solid (236 mg, 69%), m.p. 164ꢀ165 C. [α]D25= +143.8 (c 1.00, CHCl3); IR
(film) νmax 2961, 2925, 2853, 1678, 1604, 1492, 1380, 1255, 1116, 1104, 1084, 850,
1
743 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.54ꢀ7.48 (m, 1H), 7.29ꢀ7.24 (m, 1H),
7.23ꢀ7.14 (m, 4H), 7.12ꢀ7.08 (m, 1H), 7.05ꢀ7.00 (m, 1H), 6.15 (s, 1H), 3.92 (d, J =
18.8 Hz, 1H), 3.67 (d, J = 18.8 Hz, 1H), 2.31 (s, 3H) 1.15 (s, 9H) ppm; 13C NMR (100
MHz, CDCl3) δ 174.5, 140.2, 138.8, 137.8, 130.5, 128.8, 128.4, 127.9, 127.8, 127.6,
127.2, 126.2, 123.3, 60.4, 53.5, 39.8, 22.8, 21.7 ppm; HRMS (ESIꢀOrbitrap) m/z:
[M+H]+ calcd for C20H24NO2S: 342.1522, found: 342.1521.
(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ1ꢀ(oꢀtolyl)ꢀ1,4ꢀdihydroisoquinolinꢀ3(2H)ꢀone (11k)
o
White solid (270 mg, 79%), m.p. 113ꢀ115 C. [α]D25= +206.3 (c 1.00, CHCl3); IR
(film) νmax 2963, 2926, 2855, 1670, 1494,1393, 1378, 1304, 1269, 1174, 1100, 1081,
1
859, 745 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.45ꢀ7.39 (m, 1H), 7.29ꢀ7.25 (m, 1H),
7.22ꢀ7.10 (m, 6H), 6.46 (s, 1H), 4.35 (d, J = 20.0 Hz, 1H), 3.79 (d, J = 20.0 Hz, 1H),
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2.71 (s, 3H) 1.00 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 173.2, 141.0, 136.7,
135.4, 131.7, 129.6, 128.2, 127.9, 127.7, 127.3, 126.7, 126.7, 126.3, 61.0, 49.9, 39.4,
22.8, 20.8 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for C20H24NO2S: 342.1522,
found: 342.1520.
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(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ1ꢀ(2ꢀmethoxyphenyl)ꢀ1,4ꢀdihydroisoquinolinꢀ3(2H)ꢀone
(11l)
White solid (236 mg, 66%), m.p. 52ꢀ54 oC. [α]D26= +152.6 (c 0.50, CHCl3); IR (film)
νmax 2963, 2924, 1674, 1489, 1463, 1386, 1243, 1105, 1083, 1026, 915, 753 cmꢀ1; 1H
NMR (400 MHz, CDCl3) δ 7.67ꢀ7.61 (m, 1H), 7.33ꢀ7.29 (m, 1H), 7.25ꢀ7.16 (m, 3H),
7.12ꢀ7.07 (m, 1H), 6.95ꢀ6.85 (m, 2H), 6.57 (s, 1H), 4.10 (d, J = 19.2 Hz, 1H), 3.90 (s,
3H), 3.75 (d, J = 19.6 Hz, 1H), 1.06 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ
175.0, 156.5, 136.3, 129.3, 127.6, 127.4, 127.1, 127.0, 120.6, 111.5, 60.5, 55.5, 48.7,
39.6, 22.8 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for C20H24NO3S: 358.1471,
found: 358.1475.
(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ1ꢀ(naphthalenꢀ1ꢀyl)ꢀ1,4ꢀdihydroisoquinolinꢀ3(2H)ꢀone
(11m)
o
White solid (264 mg, 70%), m.p. 151ꢀ153 C. [α]D26= +337.3 (c 1.00, CHCl3); IR
(film) νmax 2961, 2922, 2857, 1672, 1510, 1393, 1366, 1349, 1266, 1164, 1120, 1106,
1079, 914, 863, 788, 772, 756, 739 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.75ꢀ8.70 (m,
1H), 7.88ꢀ7.84 (m, 1H), 7.78ꢀ7.68 (m, 2H), 7.61ꢀ7.50 (m, 3H), 7.44ꢀ7.39 (m, 1H),
7.18ꢀ7.08 (m, 4H), 4.35 (d, J = 20.0 Hz, 1H), 3.90 (d, J = 19.6 Hz, 1H), 0.95 (s, 9H)
ppm; 13C NMR (100 MHz, CDCl3) δ 174.2, 138.5, 136.4, 134.4, 130.3, 129.5, 129.3,
128.9, 128.2, 127.8, 127.4, 127.1, 126.3, 126.0, 125.3, 123.6, 60.8, 48.4, 39.5, 22.8
ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for C23H24NO2S: 378.1522, found:
378.1523.
(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ1ꢀ(naphthalenꢀ2ꢀyl)ꢀ1,4ꢀdihydroisoquinolinꢀ3(2H)ꢀone
(11n)
White solid (272 mg, 72%), m.p. 95ꢀ97 oC. [α]D25= +120.5 (c 1.00, CHCl3); IR (film)
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νmax 2963, 2926, 2855, 1750, 1677, 1244, 1107, 1083, 856, 741 cmꢀ1; H NMR (400
MHz, CDCl3) δ 7.83ꢀ7.76 (m, 4H), 7.62ꢀ7.57 (m, 1H), 7.52ꢀ7.44 (m, 3H), 7.30ꢀ7.24
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(m, 1H), 7.23ꢀ7.17 (m, 1H), 7.12ꢀ7.07 (m, 1H), 6.35 (s, 1H), 3.98 (d, J = 18.4 Hz, 1H),
3.72 (d, J = 18.4 Hz, 1H), 1.16 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 174.5,
137.4, 133.0, 132.5, 130.6, 129.2, 128.0, 128.0, 127.8, 127.7, 127.6, 126.8, 126.5,
126.2, 124.7, 124.5, 60.4, 53.6, 39.7, 22.8 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+
calcd for C23H24NO2S: 378.1522, found: 378.1526.
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(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ6,7ꢀdimethoxyꢀ1ꢀphenylꢀ1,4ꢀdihydroisoquinolinꢀ3(2H)ꢀ
one (14a)
White solid (201 mg, 52%), m.p. 153ꢀ155 oC. [α]D25= +41.1 (c 1.00, CHCl3); IR (film)
νmax 3012, 2963, 2931, 2865, 2833, 1676, 1515, 1379, 1300, 1251, 1123, 1104, 753
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cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.38ꢀ7.30 (m, 4H), 7.25ꢀ7.20 (m, 1H), 6.98 (s,
1H), 6.59 (s, 1H), 6.09 (s, 1H), 3.93ꢀ3.85 (m, 4H), 3.81 (s, 3H), 3.61 (d, J = 18.8 Hz,
1H), 1.13 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 174.4, 148.7, 148.3, 140.8,
129.8, 129.0, 127.5, 126.2, 122.3, 110.6, 109.4, 60.3, 56.2, 56.1, 53.3, 39.1, 22.8 ppm;
HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for C21H26NO4S: 388.1577, found:
388.1579.
(S)ꢀ1ꢀ([1,1'ꢀBiphenyl]ꢀ4ꢀyl)ꢀ2ꢀ((R)ꢀtertꢀbutylsulfinyl)ꢀ6,7ꢀdimethoxyꢀ1,4ꢀdihydroisoq
uinolinꢀ3(2H)ꢀone (14b)
Colorless oil (352 mg, 76%). [α]D25= +44.0 (c 1.00, CHCl3); IR (film) νmax 2959, 2930,
2861, 2830, 1676, 1516, 1376, 1250, 1103, 1080, 839, 757 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.58ꢀ7.52 (m, 4H), 7.45ꢀ7.39 (m, 4H), 7.36ꢀ7.30 (m, 1H), 7.02 (s, 1H), 6.61
(s, 1H), 6.14 (s, 1H), 3.95ꢀ3.88 (m, 4H), 3.83 (s, 3H), 3.63 (d, J = 18.8 Hz, 1H), 1.17
(s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 174.4, 148.8, 148.4, 140.4, 140.1, 139.6,
129.8, 128.9, 127.6, 127.0, 126.7, 122.4, 110.7, 109.3, 60.4, 56.3, 56.1, 53.1, 39.2,
22.9 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for C27H30NO4S: 464.1890,
found: 464.1892.
(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ1ꢀ(3ꢀfluorophenyl)ꢀ6,7ꢀdimethoxyꢀ1,4ꢀdihydroisoquinol
inꢀ3(2H)ꢀone (14c)
Colorless oil (328 mg, 81%). [α]D25= +34.8 (c 1.00, CHCl3); IR (film) νmax 2961, 2928,
1
2853, 1677, 1515, 1464, 1376, 1250, 1224, 1123, 1104, 757 cm−1; H NMR (400
MHz, CDCl3) δ 7.33ꢀ7.27 (m, 1H), 7.17ꢀ7.13 (m, 1H), 7.08ꢀ7.03 (m, 1H), 6.96ꢀ6.90
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(m, 2H), 6.60 (s, 1H), 6.06 (s, 1H), 3.91 (s, 3H), 3.88ꢀ3.80 (m, 4H), 3.62 (d, J = 18.8
Hz, 1H), 1.14 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 174.3, 163.1 (d, J = 246.6
Hz), 149.0, 148.5, 143.6 (d, J = 6.2 Hz), 130.7 (d, J = 8.2 Hz), 129.2, 122.4, 121.9 (d,
J = 2.8 Hz), 114.7 (d, J = 20.9 Hz), 113.6 (d, J = 22.3 Hz), 110.7, 109.4, 60.5, 56.4,
56.2, 52.9 (d, J = 1.4 Hz), 39.1, 22.9 ppm; 19F NMR (376 MHz, CDCl3) δ ꢀ111.1 ppm;
HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for C21H25FNO4S: 406.1483, found:
406.1486.
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(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ6,7ꢀdimethoxyꢀ1ꢀ(3ꢀ(trifluoromethyl)phenyl)ꢀ1,4ꢀdihydr
oisoquinolinꢀ3(2H)ꢀone (14d)
Colorless oil (296 mg, 65%). [α]D25= +30.9 (c 1.00, CHCl3); IR (film) νmax 2963, 2933,
1
2863, 2837, 1678, 1516, 1465, 1330, 1251, 1167, 1125, 1105, 1076, 757 cm−1; H
NMR (400 MHz, CDCl3) δ 7.64ꢀ7.60 (m, 1H), 7.58ꢀ7.44 (m, 3H), 6.97 (s, 1H), 6.62
(s, 1H), 6.14 (s, 1H), 3.91 (s, 3H), 3.85ꢀ3.77 (m, 4H), 3.63 (d, J = 18.8 Hz, 1H), 1.12
(s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 174.1, 149.1, 148.6, 142.1, 131.4 (d, J =
32.3 Hz), 129.8, 129.7, 128.9, 124.5 (d, J = 3.7 Hz), 123.8 (d, J = 270.9 Hz), 123.0 (d,
J = 3.6 Hz), 122.4, 110.8, 109.4, 60.6, 56.4, 56.2, 52.9, 39.1, 22.8 ppm; 19F NMR (376
MHz, CDCl3) δ ꢀ62.8 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for
C22H25F3NO4S: 456.1451, found: 456.1450.
(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ1ꢀ(3,4ꢀdimethoxyphenyl)ꢀ6,7ꢀdimethoxyꢀ1,4ꢀdihydroiso
quinolinꢀ3(2H)ꢀone (14e)
Colorless oil (282 mg, 63%). [α]D25= +34.4 (c 1.00, CHCl3); IR (film) νmax 3002, 2957,
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2933, 2836, 1673, 1515, 1463, 1258, 1104, 1026, 757 cm−1; H NMR (400 MHz,
CDCl3) δ 6.97ꢀ6.92 (m, 1H), 6.91ꢀ6.88 (m, 1H), 6.86ꢀ6.83 (m, 1H), 6.82ꢀ6.78 (m, 1H),
6.60 (s, 1H), 6.01 (s, 1H), 3.93ꢀ3.88 (m, 4H), 3.86ꢀ3.82 (m, 9H), 3.62 (d, J = 18.8 Hz,
1H), 1.15 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 174.2, 149.3, 148.7, 148.4,
148.4, 133.6, 130.0, 122.1, 118.4, 111.3, 110.7, 109.8, 109.3, 60.5, 56.3, 56.2, 56.0,
56.0, 53.1, 39.1, 22.9 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for C23H30NO6S:
448.1788, found: 448.1787.
(S)ꢀ2ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ6,7ꢀdimethoxyꢀ1ꢀ(naphthalenꢀ2ꢀyl)ꢀ1,4ꢀdihydroisoquino
linꢀ3(2H)ꢀone (14f)
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Colorless oil (289 mg, 66%). [α]D25= +33.1 (c 1.00, CHCl3); IR (film) νmax 3010, 2961,
1
2932, 1676, 1516, 1464, 1351, 1301, 1250, 1122, 1102, 1079, 757 cmꢀ1; H NMR
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(400 MHz, CDCl3) δ 7.84ꢀ7.76 (m, 4H), 7.53ꢀ7.44 (m, 3H), 7.06 (s, 1H), 6.59 (s, 1H),
6.25 (s, 1H), 3.96 (d, J = 18.8 Hz, 1H), 3.93 (s, 3H), 3.80 (s, 3H), 3.65 (d, J = 18.8 Hz,
1H), 1.14 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 174.6, 148.8, 148.4, 137.9,
132.5, 129.5, 129.2, 128.0, 127.7, 126.8, 126.5, 124.7, 124.4, 122.5, 110.7, 109.5,
60.4, 56.3, 56.1, 53.5, 39.2, 22.9 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for
C25H28NO4S: 438.1734, found: 438.1733.
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(S)ꢀ6ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ5ꢀphenylꢀ5,8ꢀdihydroꢀ[1,3]dioxolo[4,5ꢀg]isoquinolinꢀ7(
6H)ꢀone (16a)
Colorless oil (256 mg, 69%). [α]D25= +35.4 (c 1.00, CHCl3); IR (film) νmax 3010, 2965,
1
2924, 2853, 1676, 1502, 1485, 1380, 1270, 1236, 1119, 1086, 1038, 755 cmꢀ1; H
NMR (400 MHz, CDCl3) δ 7.37ꢀ7.29 (m, 4H), 7.25ꢀ7.20 (m, 1H), 6.96 (s, 1H), 6.54
(s, 1H), 6.04 (s, 1H), 5.93 (d, J = 1.2 Hz, 1H), 5.90 (d, J = 1.2 Hz, 1H), 3.81 (d, J =
18.4 Hz, 1H), 3.55 (d, J = 18.8 Hz, 1H), 1.13 (s, 9H) ppm; 13C NMR (100 MHz,
CDCl3) δ 174.3, 147.4, 147.1, 140.4, 131.1, 129.0, 127.6, 126.3, 123.7, 108.0, 106.8,
101.5, 60.3, 53.3, 39.5, 22.8 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for
C20H22NO4S: 372.1264, found: 372.1263.
(S)ꢀ6ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ5ꢀ(3ꢀfluorophenyl)ꢀ5,8ꢀdihydroꢀ[1,3]dioxolo[4,5ꢀg]isoq
uinolinꢀ7(6H)ꢀone (16b)
Colorless oil (230 mg, 59%). [α]D25= +33.4 (c 1.00, CHCl3); IR (film) νmax 2965, 2922,
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2849, 1680, 1485, 1378, 1236, 1087, 1038, 762 cmꢀ1; H NMR (400 MHz, CDCl3) δ
7.33ꢀ7.27 (m, 1H), 7.16ꢀ7.11 (m, 1H), 7.06ꢀ7.01 (m, 1H), 6.97ꢀ6.91 (m, 2H), 6.56 (s,
1H), 6.02 (s, 1H), 5.95 (d, J = 1.2 Hz, 1H), 5.92 (d, J = 1.2 Hz, 1H), 3.78 (d, J = 18.4
Hz, 1H), 3.57 (d, J = 18.8 Hz, 1H), 1.14 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ
174.2, 163.1 (d, J = 246.3 Hz), 147.5 (d, J = 40.1 Hz), 143.1 (d, J = 6.1 Hz), 130.7 (d,
J = 8.1 Hz), 130.5, 123.8, 121.9 (d, J = 2.8 Hz), 114.7 (d, J = 20.9 Hz), 113.6 (d, J =
22.5 Hz), 108.1, 106.8, 101.6, 60.5, 52.8, 39.4, 22.8 ppm; 19F NMR (376 MHz, CDCl3)
δ ꢀ111.1 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for C20H21FNO4S: 390.1170,
found: 390.1169.
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(S)ꢀ6ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ5ꢀ(3ꢀ(trifluoromethyl)phenyl)ꢀ5,8ꢀdihydroꢀ[1,3]dioxolo[
4,5ꢀg]isoquinolinꢀ7(6H)ꢀone (16c)
Colorless oil (277 mg, 63%). [α]D25= +31.3 (c 1.02, CHCl3); IR (film) νmax 2965, 2927,
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1683, 1504, 1486, 1330, 1167, 1125, 1086, 1039, 759 cmꢀ1; H NMR (400 MHz,
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CDCl3) δ 7.61ꢀ7.58 (m, 1H), 7.56ꢀ7.44 (m, 3H), 6.96 (s, 1H), 6.58 (s, 1H), 6.09 (s,
1H), 5.96 (d, J = 1.2 Hz, 1H), 5.93 (d, J = 1.2 Hz, 1H), 3.73 (d, J = 18.8 Hz, 1H), 3.58
13
(d, J = 18.8 Hz, 1H), 1.12 (s, 9H) ppm; C NMR (100 MHz, CDCl3) δ 174.1, 147.8,
147.4, 141.6, 131.4 (d, J = 32.2 Hz), 130.2, 129.8, 129.7, 124.6 (d, J = 3.7 Hz), 123.8
(d, J = 270.8 Hz), 123.9, 122.9 (d, J = 3.7 Hz), 108.2, 106.8, 101.6, 60.5, 52.8, 39.5,
22.8 ppm; 19F NMR (376 MHz, CDCl3) δ ꢀ62.8 ppm; HRMS (ESIꢀOrbitrap) m/z:
[M+H]+ calcd for C21H21F3NO4S: 440.1138, found: 440.1139.
(S)ꢀ5ꢀ([1,1'ꢀbiphenyl]ꢀ4ꢀyl)ꢀ6ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ5,8ꢀdihydroꢀ[1,3]dioxolo[4,5ꢀg]
isoquinolinꢀ7(6H)ꢀone (16d)
White solid (412 mg, 92%), m.p. 108ꢀ110 oC. [α]D25= +40.1 (c 1.00, CHCl3); IR (film)
ν
max 2961, 2925, 2894, 1678, 1502, 1484, 1378, 1235, 1086, 1039, 757 cmꢀ1; 1H NMR
(400 MHz, CDCl3) δ 7.57ꢀ7.51 (m, 4H), 7.44ꢀ7.38 (m, 4H), 7.35ꢀ7.30 (m, 1H), 6.99 (s,
1H), 6.55 (s, 1H), 6.09 (s, 1H), 5.92 (d, J = 1.6 Hz, 1H), 5.89 (d, J = 1.6 Hz, 1H), 3.84
(d, J = 18.8 Hz, 1H), 3.57 (d, J = 18.8 Hz, 1H), 1.16 (s, 9H) ppm; 13C NMR (100
MHz, CDCl3) δ 174.3, 147.4, 147.1, 140.4, 140.1, 139.2, 131.0, 128.9, 127.7, 127.6,
127.0, 126.7, 123.8, 108.0, 106.7, 101.4, 60.3, 53.0, 39.5, 22.8 ppm; HRMS
(ESIꢀOrbitrap) m/z: [M+H]+ calcd for C26H26NO4S: 448.1577, found: 448.1579.
(S)ꢀ6ꢀ((R)ꢀtertꢀButylsulfinyl)ꢀ5ꢀ(naphthalenꢀ2ꢀyl)ꢀ5,8ꢀdihydroꢀ[1,3]dioxolo[4,5ꢀg]isoq
uinolinꢀ7(6H)ꢀone (16e)
Colorless oil (303 mg, 72%). [α]D25= +21.6 (c 1.00, CHCl3); IR (film) νmax 3008, 2969,
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2925, 1675, 1502, 1483, 1367, 1270, 1236, 1113, 1086, 1038, 757 cmꢀ1; H NMR
(400 MHz, CDCl3) δ 7.82ꢀ7.76 (m, 4H), 7.51ꢀ7.42 (m, 3H), 7.04 (s, 1H), 6.51 (s, 1H),
6.20 (s, 1H), 5.90 (d, J = 1.2 Hz, 1H), 5.86 (d, J = 1.2 Hz, 1H), 3.87 (d, J = 18.4 Hz,
1H), 3.72 (d, J = 18.8 Hz, 1H), 1.14 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ
174.4, 147.4, 147.0, 137.4, 133.0, 132.5, 130.7, 129.1, 128.0, 127.7, 126.8, 126.4,
124.6, 124.3, 123.9, 107.9, 106.8, 101.4, 60.3, 53.4, 39.5, 22.8 ppm; HRMS
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(ESIꢀOrbitrap) m/z: [M+H]+ calcd for C24H24NO4S: 422.1421, found: 422.1424.
(S)ꢀ1ꢀ(3,4ꢀDimethoxyphenyl)ꢀ6,7ꢀdimethoxyꢀ1,4ꢀdihydroisoquinolinꢀ3(2H)ꢀone (17)
A solution of compound 14e (500 mg, 1.12 mmol) in dry MeOH (10 mL) was treated
with (COCl)2 (0.95 mL, 11.20 mmol). After being stirred overnight, the reaction
mixture was concentrated and the residue was purified by flash chromatography on
silica gel to give 17 as a yellow oil (349 mg, 91%). [α]D26= +1.2 (c 0.50, CHCl3); IR
(film) νmax 2959, 2920, 2847, 1639, 1516, 1464, 1310, 1250, 1206, 1140, 1024, 840,
757 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.30 (brs, 1H), 6.88ꢀ6.83 (m, 1H), 6.82ꢀ6.78
(m, 1H), 6.71 (s, 1H), 6.66 (s, 1H), 6.38 (s, 1H), 5.57 (s, 1H), 3.89 (s, 6H), 3.83 (s,
3H), 3.71 (s, 3H), 3.69 (brs, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 169.3, 149.8,
149.4, 149.1, 148.3, 133.5, 125.8, 122.4, 120.2, 111.3, 110.4, 110.2, 109.7, 60.1, 56.2,
56.1, 56.1, 56.1, 35.3 ppm; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for C19H22NO5:
344.1492, found: 344.1493.
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General procedure for synthesis of 12: To a compound 10 (200 mg, 0.75 mmol) in
anhydrous THF (3 mL) was treated with a solution of Grignard reagents (2.3 mL, 1 M
o
in THF) and NMM (0.50 mL, 4.50 mmol) at ꢀ15 C for 2.5h. The mixture was
quenched with a saturated NH4Cl aqueous solution and extracted with EtOAc (30 mL
× 3) and the combined organic layers were washed with brine. Dried, filtered and
concentrated, the residue was purified by flash chromatography on silica gel
(PE/EA=2/1) to give 12.
(S)ꢀ3ꢀ(4ꢀmethoxyphenyl)isoindolinꢀ1ꢀone (12a)
White solid (156 mg, 87%). Enantiomer ratio: 88%. [α] D23= +76.6 (c 0.5, MeOH); IR
(film) vmax 3424, 2982, 2841, 1647, 1514, 1469, 1453, 1269, 1108, 1051, 1031, 1016,
698 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.2 Hz, 1H), 7.53ꢀ7.44 (m, 2H),
7.23ꢀ7.16 (m, 3H), 6.90ꢀ6.83 (m, 3H), 5.59 (s, 1H), 3.79 (s, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 171.1, 159.9, 148.4, 132.4, 131.0, 130.4, 128.4, 128.2, 123.8, 123.4,
114.5, 60.5, 55.5 ppm; HRMS (ESIꢀOrbitrap) m/z: [M + H]+ Calcd for C15H14NO2:
240.1019, found: 240.1020.
(S)ꢀ3ꢀ(pꢀtolyl)isoindolinꢀ1ꢀone (12b)
White solid (152 mg, 91%). Enantiomer ratio: 78%. [α]D24= +84.0 (c 0.50, MeOH);
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IR (film) vmax 3442, 3243, 2922, 1682, 1649, 1636, 1463, 1206, 1139, 1014, 735 cmꢀ1;
1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.6 Hz, 1H), 7.51ꢀ7.43 (m, 2H), 7.22 (d, J
= 7.6 Hz, 1H), 7.16ꢀ7.14 (m, 4H), 7.00 (brs, 1H), 5.59 (s, 1H), 2.33 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ 171.2, 148.3, 138.5, 135.5, 132.4, 131.0, 129.9, 128.4,
126.9, 123.9, 123.4, 60.7, 21.3 ppm; HRMS (ESIꢀOrbitrap) m/z: [M + H]+ Calcd for
C15H14NO: 224.1070, found: 224.1068.
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(S)ꢀ3ꢀ(4ꢀfluorophenyl)isoindolinꢀ1ꢀone (12c)
White solid (155 mg, 91%). Enantiomer ratio: 89%, [α]D25= +106.4 (c 0.50, MeOH);
IR (film) vmax 3214, 3078, 1717, 1508, 1469, 1223, 1137, 856, 737, 692 cmꢀ1; 19F
NMR (376 MHz, CD3OD) δ ꢀ116.1 ppm; 1H NMR (400 MHz, CD3OD) δ 7.82 (d, J =
7.6 Hz, 1H), 7.60ꢀ7.49 (m, 2H), 7.31ꢀ7.26 (m, 2H), 7.12ꢀ7.06 (m, 2H), 5.73 (s, 1H)
ppm; 13C NMR (100 MHz, CD3OD) δ 173.2, 164.1 (d, J = 243.8 Hz), 149.8, 136.1 (d,
J = 3.2 Hz), 133.6, 132.2, 129.9 (d, J = 8.4 Hz), 129.5, 124.6, 124.3, 116.8, 116.6,
61.5 ppm; HRMS (ESIꢀOrbitrap) m/z: [M + H]+ Calcd for C14H11FNO: 228.0819,
found: 228.0818.
(S)ꢀ3ꢀ([1,1'ꢀbiphenyl]ꢀ4ꢀyl)isoindolinꢀ1ꢀone (12d)
White solid (212 mg, 99%). Enantiomer ratio: 97%, [α]D21= +217.0 (c 0.10, MeOH);
IR (film) vmax 3415, 2950, 2843, 1700, 1648, 1454, 1110, 1054, 1033, 1015, 722 cmꢀ1;
1H NMR (400 MHz, CDCl3) δ 7.95ꢀ7.88 (m, 1H), 7.60ꢀ7.55 (m, 4H), 7.55ꢀ7.48 (m,
2H), 7.48ꢀ7.42 (m, 2H), 7.39ꢀ7.33 (m, 3H), 7.31ꢀ7.28 (m, 1H), 6.72 (brs, 1H),
5.70ꢀ5.67 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.0, 148.0, 141.8, 140.5,
137.5, 132.5, 130.9, 129.0, 128.6, 128.0, 127.7, 127.4, 127.2, 124.0, 123.5, 60.6 ppm;
HRMS (ESIꢀOrbitrap) m/z: [M + H]+ Calcd for C20H16NO: 286.1226, found:
286.1222.
(S)ꢀ3ꢀ(4ꢀbutylphenyl)isoindolinꢀ1ꢀone (12e)
White solid (157 mg, 79%). Enantiomer ratio: 80%, [α]D27= +70.6 (c 0.50, MeOH);
IR (film) vmax 3225, 2955, 2927, 1694, 1656, 1467, 1424, 1315, 1209, 1139, 781, 736
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.92ꢀ7.84 (m, 1H), 7.53ꢀ7.43 (m, 2H), 7.29ꢀ7.22
(m, 1H), 7.20ꢀ7.12 (m, 5H), 5.64ꢀ5.59 (m, 1H), 2.63ꢀ2.55 (m, 2H), 1.64ꢀ1.53 (m, 2H),
1.38ꢀ1.28 (m, 2H), 0.97ꢀ0.89 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.3,
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148.3, 143.5, 135.6, 132.3, 131.0, 129.2, 128.4, 126.8, 123.8, 123.4, 60.8, 35.4, 33.7,
22.5, 14.0 ppm; HRMS (ESIꢀOrbitrap) m/z: [M + H]+ Calcd for C18H20NO: 266.1539,
found: 266.1541.
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(S)ꢀ3ꢀphenylisoindolinꢀ1ꢀone (12f)
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White solid (155 mg, 99%). Enantiomer ratio: 77%, [α]D26= +124.0 (c 0.25, MeOH);
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IR (film) vmax 3445, 2841, 1634, 1449, 1194, 1053, 1033, 1014, 739, 700 cmꢀ1; H
NMR (400 MHz, CD3OD) δ 7.85ꢀ7.80 (m, 1H), 7.58ꢀ7.48 (m, 2H), 7.38ꢀ7.26 (m, 6H),
5.74ꢀ5.71 (m, 1H); 13C NMR (150 MHz, CD3OD) δ 173.3, 150.0, 140.0, 133.5, 130.0,
129.4, 127.9, 124.6, 124.3, 62.3 ppm; HRMS (ESIꢀOrbitrap) m/z: [M + H]+ Calcd for
C14H12NO: 210.0913, found: 210.0912.
(S)ꢀ3ꢀ(mꢀtolyl)isoindolinꢀ1ꢀone (12g)
White solid (142 mg, 85%). Enantiomer ratio: 88%, [α]D24= +122.4 (c 0.50, MeOH);
IR (film) vmax 3448, 2978, 2843, 1655, 1637, 1469, 1054, 1033, 1015, 727, 643 cmꢀ1;
1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.6 Hz, 1H), 7.53ꢀ7.43 (m, 2H), 7.26ꢀ7.22
(m, 2H), 7.14ꢀ7.02 (m, 4H), 5.59 (s, 1H), 2.32 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 171.4, 148.2, 139.0, 138.5, 132.3, 131.0, 129.4, 129.0, 128.4, 127.4, 124.1,
123.8, 123.4, 61.0, 21.5 ppm; HRMS (ESIꢀOrbitrap) m/z: [M + H]+ Calcd for
C15H14NO: 224.1070, found: 224.1070.
(S)ꢀ3ꢀ(3ꢀmethoxyphenyl)isoindolinꢀ1ꢀone (12h)
White solid (162 mg, 90%). Enantiomer ratio: 68%, [α]D27= +94.4 (c 0.50, MeOH);
IR (film) vmax 3444, 2963, 2918, 1688, 1659, 1635, 1469, 1045, 1035, 731, 700 cmꢀ1;
1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.2 Hz, 1 H), 7.54ꢀ7.43 (m, 2H), 7.31ꢀ7.25
(m, 2H), 7.12 (brs, 1H), 6.92ꢀ6.83 (m, 2H), 6.80ꢀ6.77 (m, 1H), 5.61 (s, 1H), 3.77ꢀ3.75
(m, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.3, 160.3, 147.9, 140.1, 132.4, 130.9,
130.3, 128.5, 123.9, 123.4, 119.2, 114.0, 112.3, 60.9, 55.4 ppm; HRMS (ESIꢀOrbitrap)
m/z: [M + H]+ Calcd for C15H14NO2: 240.1019, found: 240.1016.
(S)ꢀ3ꢀ(3ꢀfluorophenyl)isoindolinꢀ1ꢀone (12i)
White solid (147 mg, 86%). Enantiomer ratio: 88%, [α]D23= +115.2 (c 0.50, MeOH);
IR (film) vmax 3445, 2920, 1684, 1634, 1447, 1265, 1055, 1031, 1012, 733, 694 cmꢀ1;
19F NMR (376 MHz, CD3OD) δ ꢀ114.4 ppm; 1H NMR (400 MHz, CD3OD) δ 7.82 (d,
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J = 7.6 Hz, 1H), 7.60ꢀ7.49 (m, 2H), 7.41ꢀ7.31 (m, 2H), 7.13 (d, J = 7.6 Hz, 1H),
7.07ꢀ6.99 (m, 2H), 5.75 (s, 1H) ppm; 13C NMR (100 MHz, CD3OD) δ 173.3, 164.5 (d,
J = 244.1 Hz), 149.4, 143.0 (d, J = 6.8 Hz), 133.7, 132.1, 131.9 (d, J = 8.1 Hz), 129.6,
124.6, 124.4, 123.7 (d, J = 2.9 Hz), 116.1 (d, J = 21.3 Hz), 114.5 (d, J = 22.4 Hz),
61.6 ppm; HRMS (ESIꢀOrbitrap) m/z: [M + H]+ Calcd for C14H11FNO: 228.0819,
found: 228.0817.
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(S)ꢀ3ꢀ(3ꢀ(trifluoromethyl)phenyl)isoindolinꢀ1ꢀone (12j)
White solid (198 mg, 95%). Enantiomer ratio: 84%, [α]D25= +84.8 (c 0.50, MeOH);
IR (film) vmax 3445, 2920, 1722, 1645, 1634, 1340, 1304, 1110, 1014, 739, 708cmꢀ1;
19F NMR (376 MHz, CDCl3) δ ꢀ62.6 ppm; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J =
7.6 Hz, 1H), 7.68 (brs, 1H), 7.61ꢀ7.46 (m, 6H), 7.23 (d, J = 7.2 Hz, 1H), 5.71 (s, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 171.5, 147.3, 139.8, 132.7, 131.6 (d, J = 32.2
Hz), 130.8, 130.3, 129.8, 128.9, 125.6 (d, J = 4.4 Hz), 124.1, 123.9 (d, J = 270.8Hz),
123.8 (d, J = 4.2 Hz), 123.4, 60.5 ppm; HRMS (ESIꢀOrbitrap) m/z: [M + H]+ Calcd
for C15H11F3NO: 278.0787, found: 278.0789.
(S)ꢀ3ꢀ(oꢀtolyl)isoindolinꢀ1ꢀone (12k)
White solid (144 mg, 86%). Enantiomer ratio: 82%, [α]D25= +93.6 (c 0.50, MeOH);
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IR (film) vmax 3443, 2918, 1690, 1638, 1469, 1314, 1135, 1012, 737, 622 cmꢀ1; H
NMR (400 MHz, CDCl3) δ 7.90ꢀ7.87 (m, 1H), 7.52ꢀ7.44 (m, 2H), 7.23ꢀ7.19 (m, 3H),
7.15ꢀ7.09 (m, 1H), 7.04ꢀ7.02 (m, 1H), 5.92 (s, 1H), 2.44 (s, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 171.3, 148.0, 136.2, 136.1, 132.4, 131.5, 131.4, 128.4, 127.3, 124.0,
123.3, 58.1, 19.5 ppm; HRMS (ESIꢀOrbitrap) m/z: [M + H]+ Calcd for C15H14NO:
224.1070, found: 224.1068.
(S)ꢀ3ꢀ(2ꢀmethoxyphenyl)isoindolinꢀ1ꢀone (12l)
Yellow solid (165 mg, 92%). Enantiomer ratio: 62%, [α]D26= +139.4 (c 0.50, MeOH);
IR (film) vmax 3447, 2920, 2849, 1693, 1633, 1490, 1461, 1245, 1049, 1022, 739, 622
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cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.2 Hz, 1H), 7.53ꢀ7.41 (m, 3H),
7.31ꢀ7.26 (m, 1H), 7.22 (brs, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 4.0 Hz, 1H),
6.90ꢀ6.83 (m, 1H), 6.15 (s, 1H), 3.95 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
171.3, 157.3, 147.7, 132.0, 131.6, 129.4, 128.2, 126.7, 126.6, 123.9, 123.8, 121.0,
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110.9, 55.6, 54.9 ppm; HRMS (ESIꢀOrbitrap) m/z: [M + H]+ Calcd for C15H14NO2:
240.1019, found: 240.1022.
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(S)ꢀ3ꢀ(naphthalenꢀ1ꢀyl)isoindolinꢀ1ꢀone (12m)
White solid (175 mg, 90%). Enantiomer ratio: 88%, [α]D20= +376.0 (c 0.10, MeOH);
IR (film) vmax 3194, 2918, 2843, 1696, 1655, 1508, 1422, 1307, 1139, 909, 748, 723
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.19 (brs, 1H), 7.95ꢀ7.90 (m, 2H), 7.85ꢀ7.80 (m,
1H), 7.65ꢀ7.53 (m, 2H), 7.50ꢀ7.43 (m, 2H), 7.42ꢀ7.38 (m, 2H), 7.31ꢀ7.28 (m, 1H),
7.25ꢀ7.21 (m, 1H), 6.50 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.3, 147.9,
134.3, 132.3, 131.3, 131.2, 129.4, 129.2, 128.6, 127.0, 126.2, 125.8, 124.2, 123.3,
122.7 ppm; HRMS (ESIꢀOrbitrap) m/z: [M + H]+ Calcd for C18H14NO: 260.1070,
found: 260.1072.
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(S)ꢀ3ꢀ(naphthalenꢀ2ꢀyl)isoindolinꢀ1ꢀone (12n)
White solid (169 mg, 87%). Enantiomer ratio: 86%, [α]D26= +167.2 (c 0.25, MeOH);
IR (film) vmax 3193, 3051, 2843, 1695, 1656, 1469, 1346, 1199, 909, 822, 723 cmꢀ1;
1H NMR (400 MHz, CD3OD) δ 7.92 (brs, 1H), 7.89ꢀ7.80 (m, 4H), 7.61ꢀ7.45 (m, 5H),
7.32 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 5.92ꢀ5.87 (m, 1H) ppm; 13C NMR
(150 MHz, CD3OD) δ 173.4, 150.0, 137.3, 134.9, 134.8, 133.6, 132.4, 129.9, 129.5,
128.9, 128.8, 127.5, 127.5, 127.4, 124.9, 124.8, 124.3, 62.4 ppm; HRMS
(ESIꢀOrbitrap) m/z: [M + H]+ Calcd for C18H14NO: 260.1070, found: 260.1072.
1
Supporting Information: Copies of H, 19F and 13C NMR spectra, HPLC (12aꢀn)
and Xꢀray structural data (CIF) (11g; 16d). The Supporting Information is available
free of charge on the ACS Publications website at http://pubs.acs.org.
Accession Codes
CCDC 1839098 and 1839101 contain the supplementary crystallographic data for this
paper.
These
data
can
be
obtained
free
of
charge
via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk,
or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
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