Stereoselective synthesis of isoindolinones and tert-butyl sulfoxides

Article abstract of DOI:10.1016/j.tet.2017.12.035

A reaction of Grignard reagents with an optically pure N-sulfinylimine derived from methyl 2-formylbenzoate yields enantioenriched isoindolinones and tert-butyl sulfoxides. The products are formed by the addition of the nucleophile to N-sulfinylimine followed by cyclization to form N-tert-butylsulfinylisoindolinone, which readily undergoes substitution with a second equivalent of Grignard reagent. The reaction can be carried out in dichloromethane at room temperature or at elevated temperatures without any loss of stereoselectivity. The use of nucleophiles other than Grignard reagents has also been investigated.

Full text of DOI:10.1016/j.tet.2017.12.035

Accepted Manuscript
Stereoselective synthesis of isoindolinones and tert-butyl sulfoxides
Robert Kawęcki, Wojciech Stańczyk, Agnieszka Jaglińska
PII:
S0040-4020(17)31303-0
10.1016/j.tet.2017.12.035
TET 29191
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 October 2017
Revised Date: 13 December 2017
Accepted Date: 15 December 2017
Please cite this article as: Kawęcki R, Stańczyk W, Jaglińska A, Stereoselective synthesis of
isoindolinones and tert-butyl sulfoxides, Tetrahedron (2018), doi: 10.1016/j.tet.2017.12.035.
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Stereoselective synthesis of isoindolinones
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and tert-butyl sulfoxides
Robert Kawęcki*, Wojciech Stańczyk, Agnieszka Jaglińska
Siedlce University, Faculty of Science, 3 Maja 54, 08-110 Siedlce, Poland

1
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Tetrahedron
journal homepage: www.elsevier.com
Stereoselective synthesis of isoindolinones and tert-butyl sulfoxides
Robert Kawęcki*, Wojciech Stańczyk, Agnieszka Jaglińska
a Siedlce University, Faculty of Science, 3 Maja 54, 08-110 Siedlce, Poland
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A reaction of Grignard reagents with an optically pure N-sulfinylimine derived from methyl 2-
formylbenzoate yields enantioenriched isoindolinones and tert-butyl sulfoxides. The products
are formed by the addition of the nucleophile to N-sulfinylimine followed by cyclization to form
N-tert-butylsulfinylisoindolinone, which readily undergoes substitution with a second equivalent
of Grignard reagent. The reaction can be carried out in dichloromethane at room temperature or
at elevated temperatures without any loss of stereoselectivity. The use of nucleophiles other than
Grignard reagents has also been investigated.
Available online
Keywords:
isoindolinones,
sulfinamides,
2017 Elsevier Ltd. All rights reserved
.
sulfoxides,
asymmetric synthesis,
nucleophilic addition.
1. Introduction
by using a stereoselective addition of allylindium to N-
sulfinylimine 1 followed by desulfinylation and cyclization to
give 3-allylisoindolinones with excellent stereoselectivity. The
free radical approach of this reaction was described by
Rodríguez-Fernández et al.22 by using tributyltin-mediated
3-Substituted isoindolinones possess diverse biological
properties, such as anxiolytic,1 sedative-hypnotic,2 anticancer,3
antileukemic,4
antihyper-glycemic,5
antiviral6
and
antihypertensive7 properties. They are also potent neurokinin-,8
serotonin-,9 and dopamine-receptor10 inhibitors or antagonists.
For many years, they have become the target of medicinal
chemists, particularly in enantiomeric form. Most methods for
the synthesis of optically active isoindolinones are based on the
use of chiral auxiliaries. Some good examples are addition of
Grignard reagents to chiral N-substituted phthalimides,11 reaction
of chiral Schiff bases of glycine with 2-cyanobenzaldehyde,12
cyclization of chiral α-substituted benzylamines,13 and alkylation
of chiral N-acylisoindolinones.14 Catalytic methods include
Rh(I)-catalyzed arylation of 2-bromobenzaldimines followed by
aminocarbonylation,15 enantioselective addition of isoindolinones
to imines,16 aminoacid-catalyzed Mannich reaction followed by
lactamization,17 and cinchoninium-catalyzed intramolecular aza-
Michael reactions.18 A thorough review of asymmetric syntheses
of 3-substituted isoindolinones was published by Massa et al. 19
o
isopropyl iodide addition at -78 C to N-sulfinylimine 1. Our
procedure allows preparation of numerous derivatives of 3-
substituted isoindolinones, not only limited to 3-allyl or 3-
isopropyl.
The
starting
methyl
2-[(tert-butyl-N-sulfinylimine)-
methyl]benzoate
1
can be conveniently prepared by the
condensation of commercially available optically pure tert-
butylsulfinamide with methyl 2-formylbenzoate in the presence
of KHSO4 (Scheme 1).23 The enantiomeric excess of N-
sulfinylimine 1 was 98%.
O
S
N
-Bu
t
O
CHO
t-BuSNH2
(R) or (S)
KHSO4, toluene
45 oC, 3 h, rt, 16 h
96%
CO2Me
CO2Me
In this paper, we propose a straightforward method for the
preparation of enantioenriched isoindolinones using Ellman’s
tert-butylsulfinamide methodology.20 The same reaction may be
used for obtaining optically pure tert-butyl sulfoxides.
1
Scheme 1. Substrate preparation.
Unexpectedly, we found that the desired isoindolinones could
be formed directly in one step by using Grignard reagents. The
second product of this reaction was found to be tert-butyl
sulfoxide (Scheme 2). Apparently, Grignard reagent after the
addition to the C=N bond further reacted, yielding a substitution
product at the sulfur atom.
2. Results and discussion
We tried to obtain isoindolinones by using the following-three
step procedure: addition of Grignard reagent to N-sulfinylimine 1
derived from 2-carboxybenzaldehyde, removal of the sulfinyl
group from the nitrogen atom, and cyclization. A similar
stepwise procedure was described earlier by Xu and coworkers21

2
Tetrahedron
provided low ee of isoindolinone (Table 2, entry 5). Therefore,
ACCEPTED MANUSCRIPT
O
S
we used solutions of Grignard reagents in diethyl ether.
R
N
RMgBr
(2.5-3 equiv)
t-Bu
However, the ee remained medium. Decreasing the reaction
temperature did not improve the results. The highest
stereoselectivity was observed at 40 C. The ee did not change
O
S
R
NH
OCH3
+
o
CH2Cl2
temp.
t-Bu
O
O
significantly after 15 min and after several hours (Table 3, entry
3-5). Similar temperature dependence was observed for the BuLi
addition to O-protected N-trimethylsilyl imines of (2S)-lactal.24
3
(S)-1
2
O
S
Scheme 2. Addition of Grignard reagents to N-sulfinylimine
1.
I
O
N
Nu
t-Bu
S
-Bu
t
The proposed mechanism is shown in Scheme 3. We assume
that nucleophile addition to the N-sulfinylimine is followed by
N
Nu
CO2CH3
OCH3
cyclization
to
form
the
corresponding
N-tert-
O
butylsulfinylisoindolinone, which finally undergoes a SN2-type
substitution with the second equivalent of Grignard reagent to
form the products.
II
O
S
N
Nu
Nu
t-Bu
O
S
N
When we used more than two equivalents of an
organomagnesium compound, the yield was excellent and the
only products were isoindolinone and tert-butyl sulfoxide. The
results are presented in Table 1. The enantioselectivity of
isoindolinones strongly depends on the reaction conditions. The
effects of different solvents, temperature, and additives are
presented in Tables 2 and 3.
t-Bu
OCH3
-CH3O
O
O
III
Nu
NH
Nu
Nu
O
S
O
SN2
+H+
Nu
+
N
S
t-Bu
t-Bu
O
O
The best results were obtained when using dichloromethane as
solvent (Table 2, entry 3). Additives, such as AlMe3, CuI, or
TMEDA, did not improve the ee. The presence of THF was also
unfavorable. Solutions of organomagnesium reagents in THF
Scheme 3. Reaction mechanism.
Table 1 Synthesis of 3-substituted isoindolinones 2a
Entry
N-Sulfinylimine
R
Temp. oC
Isoindolinone
(S)-2a
Yieldb, %
90
Ee, %
68
1
(R)-1
Me
20
40
40
0
2
(R)-1
i-Pr
(S)-2b
(R)-2c
(R)-2d
(S)-2e
90
58
3
(S)-1
Bu
95
71
4
(S)-1
Hex
76
55
5
(R)-1
Bn
40
40
20
0
71
91
6
(R)-1
Ph
(S)-2f
62
78
7
(S)-1
2-MeOC6H4
4-ClC6H4
4-ClC6H4
p-Tol
(S)-2g
88
11
8
(S)-1
(R)-2h
(S)-2h
(R)-2i
99
80
9
(R)-1
40
40
91
81
10
(S)-1
90
82
a The reactions were carried out on a 0.19-0.75 mmol scale under argon for 90 min except for entry 1, 120 min, entries 6 and 9, 20 min. 3 equiv of
Grignard reagent were used.
b Isolated yield.
Table 2 Solvent and additives effect upon the addition of Grignard reagent for the preparation of isoindolinone 2c a
Entry
N-Sulfinylimine
Grignard reagent
BuMgBr / Et2O
BuMgBr / Et2O
BuMgBr / Et2O
BuMgBr / Et2O
BuMgCl / THF
BuMgBr / Et2O
BuMgBr / Et2O
Solvent / Additive
Temp. oC
Yieldb, %
Ee, %
1
2
3
4
5
6
7
(R)-1
THF
0
66
66
95
69
98
93
99
9
(R)-1
PhMe
40
40
0
5
(S)-1
CH2Cl2
71
60
20
16
57
(R)-1
CH2Cl2 / AlMe3
CH2Cl2 / AlMe3
CH2Cl2 / TMEDA
CH2Cl2 / CuI
(R)-1
0
(S)-1
0
(S)-1
0
a The reaction was carried out on a 0.374 mmol scale under an atmosphere of argon. 3 equiv of Grignard reagent were used.
b Isolated yield.

3
Table 3 Temperature effect on Grignard addition for the preparation of isoindolinone 2c a
ACCEPTED MANUSCRIPT
Entry
N-Sulfinylimine
Grignard reagent
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Temp., oC/ time
-20 / 180 min
0 / 180 min
Yieldb, %
Ee, %
30
1
2
3
4
5
(R)-1
BuMgBr
76
87
98
97
99
(R)-1
BuMgBr
50
(R)-1
BuMgBr
40 / 15 min
68
(R)-1
BuMgBr
40 / 30 min
67
(R)-1
BuMgBr
40 / 240 min
70
a The reaction was carried out on a 0.374 mmol scale under an atmosphere of argon. 3 equiv of Grignard reagent were used.
b Isolated yield.
Table 4 Synthesis of tert-butyl sulfoxides 3 a
Entry
N-Sulfinylimine
R
Temp., oC
Sulfoxide
(S)-3c
(R)-3c
(S)-3e
(R)-3f
(R)-3g
(S)-3g
(S)-3h
(S)-3i
Yieldb, %
Ee, %
98
1
2
3
4
5
6
7
8
(S)-1
Bu
0
99
99
79
55
95
88
95
96
(R)-1
Bu
0
99
(S)-1
Bn
40
-20
20
40
40
40
93
(S)-1
Ph
99
(S)-1
2-MeOC6H4
2-MeOC6H4
4-ClC6H4
p-Tol
98
(R)-1
98
(R)-1
97
(R)-1
95
a The reaction was carried out on a 0.374 mmol scale under an atmosphere of argon. 3 equiv of Grignard reagent were used.
b Isolated yield.
o
at room temperature or 0 C. Considering that the ee of the N-
sulfinylimine was 98 %, there was no loss of optical purity. At 40
oC, the ee decreased to 93-95 % (Table 4, entries 3 and 8). The
presented approach might be useful because tert-butyl sulfoxides
are valuable substrates in many reactions.27 To the best of our
knowledge, our synthesis of tert-butylsulfoxides can compete
with existing methods in the literature.
i-Pr
t-Bu
N
S
O
O
4
Figure 1 Transition product 4
The reaction of N-sulfinylimine 1 with strong nucleophiles
was found very general. For example, the reaction with sodium
methanolate yields 3-methoxy isoindolinone 5 (Scheme 4). The
crude reaction mixture can be purified by simple trituration with
hexane, which dissolves methyl tert-butylsulfinate.
We could isolate the transition product 4 (major diastereomer)
by using substoichiometric amounts of isopropylmagnesium
o
chloride (Figure 1). Usually, at 40 C the reaction was complete
o
in minutes; however, at 0 C and at room temperature, we used
longer reaction times to obtain a better yield. The configuration at
C-3 was established based on the optical rotation discussed in
earlier literature. It was in agreement with the chelated transition
state mechanism of the addition of Grignard reagents to N-
sulfinylimines as proposed by Ellman25 and Davis.26 The yield of
isoindolinones is usually very high, but the chromatographic
isolation of the product might be difficult in some cases (e.g., 3-
hexylisoindolinone 2d). Isoindolinones with an aromatic
substituent at C-3 may be purified by simple trituration with a
hexane-diethyl ether mixture. tert-Butyl sulfoxides are easily
soluble in such a solution. Poor results were obtained with
ethynyl and allylmagnesium bromides. Chelating substituents,
such as 2-methoxyphenyl, significantly lowered the ee. The use
of n-butyllithium instead of n-butylmagnesium bromide also
results in low ee for the isoindolinone.
O
S
N
t-Bu
OCH3
MeONa, MeOH
16 h, rt
N
H
CO2Me
O
99%
5 70% ee
1
Scheme 4 Synthesis of 3-methoxyisoindolinone
O
O
S
N
t-Bu
S
H3C
CH2Li / THF
NH
-30 oC - rt, 1.5 h
44%
CO2CH3
O
Moreover, the present reaction was particularly useful for the
synthesis of enantiomerically pure tert-butyl sulfoxides 3 (Table
4). They were formed by a nucleophilic substitution of N-
sulfinylisoindolinone (Scheme 2). The isoindolinone moiety
seemed to be an excellent leaving group. Usually, the yields and
the ee of sulfoxides were high when the reaction was carried out
1
6
Scheme 5 Addition of dimsyl lithium
.

4
Tetrahedron
ACCEPTED MANUSCRIPT
O
O
BuO
BuO
LiHMDS
NH
+
P
-Bu
t
or BuLi
S
O
0 oC, 2 h
S
N
O
t-Bu
8
7
O
+
OCH3
HP(OBu)2
O
OBu
OBu
P
O
1.
K2CO3, CH2Cl2, rt
NH
2. HCl, EtOH
3. NaHCO3 aq
O
9
Scheme 6. Addition of dibutyl phosphonate
1
The reaction of dimsyl lithium with N-sulfinylimine 1 yields
3-methyleneisoindolinone 6 (Scheme 5). In this example, the
addition of a sulfoxide anion is followed by the elimination of
sulfenic acid. An analogous reaction with a carbanion obtained
from dimethyl sulfone failed. The reaction of N-sulfinylimine 1
and a phosphonate anion generated by deprotonation with
LiHMDS or n-BuLi unexpectedly yielded phthalimide as the
main product (Scheme 6). We assumed that the addition of
phosphonate to N-sulfinylimine was followed by the elimination
of sulfenic acid and a reaction at the phosphorus atom to yield
phthalimide 7 and O,O-dibutyl-S-tert-butyl phosphorothioate 8.
signals (chloroform δ = 7.26 and 77.0 ppm for H NMR and 13C
NMR respectively). High-resolution mass spectra (HRMS) were
obtained using an electrospray ionization (ESI) source. HPLC
was performed using cyclohexane-isopropanol mixture at flow
rate 0.5 mL/min and UV detection (230 nm or 250 nm).
Commercial chiral ODH, AD and OJ type columns 5 µm,
250x4.6 mm were used.
4.1. (R)-Methyl 2-[(N-t-butylsulfinylimine)methyl] benzoate (1)
To a solution of (R)-tert-butylsulfinamide (400 mg, 3.3 mmol)
and methyl 2-formylbenzoate (800 mg, 4.95 mmol) in dry
toluene (80 mL) was added potassium hydrogen sulfate (900 mg,
The use of K2CO3 as a base resulted in the addition of a
phosphonate anion to the C=N bond without subsequent
cyclization. Routine removal of the tert-butylsulfinyl group with
ethanolic HCl and alkalization yielded isoindolinone-3-
phosphonate 9 in the racemic form.
o
6.6 mmol). The mixture was stirred at 45 C for 3 hrs and 16 hrs
at rt. After filtration the solution was evaporated to give yellow
oil. Chromatography on silica gel using AcOEt:hexane 1:2.5
(v/v) gave the title compound as white crystals (0.767 g, 86%).
Analogously was obtained second enantiomer. Spectroscopic
data identical to reported:22 1H NMR (400 MHz, CDCl3) δ: 1.29
(s, 9H, t-Bu); 3.95 (s, 3H, OCH3); 7.52-7.64 (m, 2H, Ar); 7.95
(dd, J =7.5 Hz, J =1.2 Hz, 1H, Ar); 8.02 (dd, J =7.9 Hz, J =1.2
Hz, 1H, Ar); 9.22 (s, 1H, CH=N). 13C NMR (CDCl3) δ: 22.6,
52.6, 57.9, 128.9, 130.4, 131.2, 131.3, 132.1, 134.5, 162.5, 167.0.
3. Conclusions
An efficient one-step method for the synthesis of
enantioenriched 3-substituted isoindolinones and tert-butyl
sulfoxides from methyl 2-[(N-tert-butylsulfinylimine)methyl]
benzoate and Grignard reagents was developed. The procedure is
robust, reliable, and straightforward. High stereoselectivity was
observed at room temperature and at 40 oC. In the case of poorly
soluble 3-aryl substituted isoindolinones, the purification did not
require chromatography. N-tert-Butylsulfinyl-isoindolinone is a
very good sulfinylating agent, so the reaction with Grignard
reagents produced enantiopure tert-butyl sulfoxides in good
yields. The use of sodium methanolate as a nucleophile yielded
3-methoxyisoindolinone. The reaction with dimsyl lithium or
lithium phosphonates yielded addition products that underwent
further transformations.
4.2. General procedure for the addition of Grignard reagents to
N-sulfinylimine (1).
To a solution of N-sulfinylimine 1 (100 mg, 0.374 mmol) in
dry dichloromethane (6 mL) was added etheral solution of
Grignard reagent (1.12 mmol) at temperature indicated in Table
1. Reaction was quenched with aqueous NH4Cl solution (6 mL).
The organic layer was separated and aqueous layer was extracted
with dichloromethane (3 x 10 mL). Organic extracts were dried
with MgSO4, filtered and evaporated. In the case of 3-aryl
substituted isoindolinones resulting crystals may be triturated
with hexane-diethyl ether (1:1) mixture to wash out t-butyl
sulfoxide. Washings were further purified using column
chromatography on silica gel.
4. Experimental
All reactions containing moisture or oxygen sensitive reagents
were performed under argon using ballons. Tetrahydrofuran and
diethyl ether were dried with sodium in the presence of
benzophenone. Dichloromethane was dried with CaH2. Methyl 2-
formylbenzoate was obtained by alkylation of 2-formylbenzoic
acid with CH3I.28 Butylmagnesium bromide in diethyl ether was
obtained using standard procedure. Racemic sulfoxides for HPLC
4.3. (S)-3-Methyl-2,3-dihydro-1H-isoindolin-1-one (2a).
Following general procedure, (R)-N-sulfinylimine 1 (100 mg,
0.374 mmol) and 3M etheral solution of methylmagnesium
bromide (0.49 mL, 1.48 mmol) were reacted for 120 min at rt.
Product was purified using column chromatography on silica gel
acetone:hexane 1:1 (v/v) yielding 46 mg of white crystals (90%).
The spectroscopic data matched those reported in the literature:30
1H NMR (400 MHz, CDCl3) δ: 1.51 (d, J = 6.9 Hz, 3H, CH3),
4.70 (q, J = 6.9 Hz, 1H, C3-H), 7.17 (br, 1H, N-H), 7.42-7.49 (m,
2H, Ar), 7.57 (td, J = 1.2 Hz, 7.5 Hz, 1H, Ar), 7.85 (dt, J = 0.8
Hz, 1.6 Hz, 1H, Ar). 13C NMR (CDCl3) δ: 20.3, 52.5, 122.2,
standards
were
prepared
from
rac-tert-butyl
tert-
butanethiosulfinate and Grignard reagents according to known
procedure.29 All other reagents were purchased from commercial
sources and used without further purification. Column
chromatography was performed using Acros Organics 60 Å silica
gel with the indicated solvents. NMR spectra were recorded on a
400 MHz instrument and were referenced to residual solvent

5
17
123.7, 128.1, 131.5, 131.9, 148.9, 170.8. [α]D20 = -18.7 (c = 0.97,
CH2Cl2). lit. [α]D = +42.7 (c = 0.43, CHCl3) for (R)
ACCEPTED MANUSCRIPT
CH2Cl2). Lit. [α]D18 = +10.3 (c =0.67, CHCl3) for (R) isomer.30
4.4. (S)-3-Isopropyl-2,3-dihydro-1H-isoindolin-1-one (2b).
enantiomer.30
4.8. (S)-3-Phenyl-2,3-dihydro-1H-isoindolin-1-one (2f).
Following general procedure, (R)-N-sulfinylimine 1 (100 mg,
Following general procedure, (R)-N-sulfinylimine 1 (60 mg,
0.374 mmol) and 2M etheral solution of isopropylmagnesium
bromide (1.12 mmol) were reacted for 90 min at 40 C. Product
0.225 mmol) and 3M etheral solution of phenylmagnesium
bromide (0.23 mL, 0.674 mmol) were reacted at 40 C for 15
o
o
was purified using column chromatography on silica gel
AcOEt:Hexane 1:1 (v/v) yielding 59 mg (90%) of white crystals.
The spectroscopic data matched those reported in the literature.30
1H NMR (400 MHz, CDCl3) δ: 0.72 (d, J = 6.9 Hz, 3H, CH3),
1.09 (d, J = 6.9 Hz, 3H, CH3), 2.26 (dsep, J = 3.7 Hz, 7.0 Hz, 1H,
C-H), 4.56 (d, J = 3.7 Hz, 1H, N-C-H), 7.32 (br, 1H, N-H), 7.41-
7.48 (m, 2H, Ar), 7.55 (td, J = 1.2 Hz, 7.4 Hz, 2H, Ar), 7.85 (d, J
= 7.4 Hz, 1H, Ar). 13C NMR (CDCl3) δ: 15.8, 19.5, 31.7, 62.4,
122.6, 123.6, 127.9, 131.6, 132.5, 146.6, 171.9. [α]D20 = -21.78 (c
min. Product was purified using column chromatography on
silica gel using acetone:hexane 1:3 (v/v) to give 29 mg of white
crystals (62%). The spectroscopic data matched those reported in
the literature:30 1H NMR (400 MHz, CDCl3) δ: 5.62 (s, 1H, C3-
H); 6.39 (br, 1H, N-H); 7.22-7.29 (m, 3H, Ar); 7.31-7.39 (m, 3H,
Ar); 7.45-7.54 (m, 2H, Ar); 7.90 (dd, J = 1.6 Hz, 6.2 Hz, 1H, Ar).
13C NMR (CDCl3) δ: 60.7, 123.3, 123.8, 126.8, 128.4, 128.5,
20
129.1, 130.7, 132.3, 138.4, 147.9, 171.0. [α]D = +50.9 (c =
17
0.62, CH2Cl2). Lit. [α]D =-81.1 (c 0.34, CHCl3) for (R)
18
= 0.895, CH2Cl2). lit. [α]D = +22.6 (c = 0.70, CHCl3) for
enantiomer.30
enantiomer (R).30
4.9. (S)-3-(2-Methoxyphenyl)-2,3-dihydro-1H-isoindolin-1-one
(2g).
4.5. (R)-3-Butyl-2,3-dihydro-1H-isoindolin-1-one (2c).
Following general procedure, (S)-N-sulfinylimine 1 (50 mg,
Following general procedure, (S)-N-sulfinylimine 1 (100 mg,
0.374 mmol) and 2M etheral solution of n-butylmagnesium
bromide (0.561 mL, 1.123 mmol) were reacted for 90 min at 40
oC. Product was purified using column chromatography on silica
gel AcOEt:Hexane 1:1 v/v) yielding 69 mg of white crystals
(98%). The spectroscopic data matched those reported in the
literature:30 1H NMR (400 MHz, CDCl3) δ: 0.90 (t, J = 7 Hz, 3H,
CH3), 1.22-1.50 (m, 4H, CH2), 1.59-1.70 (m, 1H, CH2), 1.90-2.0
(m, 1H, CH2), 4.62 (dd, J = 4.5 Hz, 7.8 Hz, 1H, C3-H), 7.37 (br,
1H, N-H), 7.41-7.48 (m, 2H, Ar), 7.56 (td, J = 1.2 Hz, 7.4 Hz,
1H, Ar), 7.84 (d, J = 7.4 Hz, 1H, Ar). 13C NMR (CDCl3) δ: 13.9,
0.188
mmol)
and
1M
etheral
solution
of
o-
methoxyphenylmagnesium bromide (0.56 mL, 0.56 mmol) were
o
reacted at 20 C for 90 min. Product was purified using column
chromatography on silica gel using AcOEt:hexane 1:1 (v/v) to
give 40 mg of white crystals (88%). The spectroscopic data
matched those reported in the literature:32 1H NMR (400 MHz,
CDCl3) δ: 3.95 (s, 3H, OCH3), 6.13 (s, 1H, C3-H), 6.58 (br, 1H,
N-H), 6.87 (td, J = 0.8 Hz, 7.4 Hz, 1H, Ar), 6.98 (dd, J = 0.8 Hz,
8.2 Hz, 1H, Ar), 7.05 (dd, J = 1.6 Hz, 7.4 Hz, 1H, Ar), 7.26-7.32
(m, 1H, Ar), 7.39-7.49 (m, 2H, Ar), 7.52 (td, J = 1.2 Hz, 7.4 Hz,
1H, Ar), 7.88 (dd, J = 1.2 Hz, 7.0 Hz, 1H, Ar). 13C NMR (CDCl3)
δ: 54.6, 55.5, 110.7, 120.9, 123.7, 123.8, 126.5, 128.2, 129.4,
131.5, 131.9, 147.3, 157.2, 170.8.
22.6, 27.6, 34.2, 57.0, 122.4, 123.7, 127.9, 131.7, 131.9, 147.8,
17
171.3. [α]20 = +21.62 (c = 0.555, CH2Cl2). lit. [α]D = +30.7 (c
D
= 0.55, CHCl3) for (R) isomer.30
4.10. (R)-3-p-Chlorophenyl-2,3-dihydro-1H-isoindolin-1-one
4.6. (R)-3-Hexyl-2,3-dihydro-1H-isoindolin-1-one (2d).
(2h).
Following general procedure, (S)-N-sulfinylimine 1 (202 mg,
0.75mmol) and 2M etheral solution of n-hexylmagnesium
bromide (1.13 mL, 2.25 mmol) were reacted for 90 min at 0 C
Following general procedure, (S)-N-sulfinylimine 1 (80 mg,
0.3 mmol) and 1M etheral solution of p-chlorophenylmagnesium
bromide (0.9 mL, 0.9 mmol) were reacted at 0 C for 90 min.
o
o
and left overnight at rt. Product was purified using column
chromatography on silica gel (acetone-hexane 1:2 v/v) yielding
120 mg of white crystals (76%). The spectroscopic data matched
those reported in the literature:31 1H NMR (400 MHz, CDCl3): δ:
0.86 (t, J =6.8Hz, 3H, CH3); 1.23-1.50 (m, 9H); 1.58-1.69 (m.
1H); 1.89-2.0 (m. 1H); 4.61 (dd, J =4.6Hz, 7.9 Hz, 1H, C3-H);
7.13 (br. 1H, NH); 7.41-7.48 (m, 2H, Ar.); 7.56 (dt, J =7.5Hz,
1.2Hz, 1H, Ar); 7.84 (d, J =7.5Hz, 1H, Ar). 13C NMR (CDCl3): δ
= 14.0; 22.5; 25.5; 29.2; 31.6; 34.6; 56.9; 122.4; 123.7; 128.0;
Product was purified using column chromatography on silica gel
using acetone:hexane 1:3 (v/v) to give 73 mg of white crystals
(99%). The spectroscopic data matched those reported in the
literature:33 1H NMR (400 MHz, CDCl3) δ: 5.60 (s, 1H, C3-H),
6.74 (br, 1H, N-H), 7.18-7.24 (m, 3H, Ar), 7.30-7.35 (m, 2H,
Ar), 7.45-7.55 (m, 2H, Ar), 7.89 (dd, J = 1.6 Hz, 6.6 Hz, 1H, Ar).
13C NMR (CDCl3) δ: 60.0, 123.2, 123.9, 128.2, 128.6, 129.3,
130.6, 132.5, 134.4, 136.9, 147.5, 170.9. [α]D20 = -113.7 (c = 0.7,
CH2Cl2). lit. [α]D20 =+ 42.2 (c 1.0, CH2Cl2).33
20
131.7; 131.8; 147.7; 170.6. [α]D = +37.4 (c = 1.7, CH2Cl2). lit.
[α]D18 = +26.9 (c = 0.77, CHCl3) for (R) isomer.30
4.11. (R)-3-p-Tolyl-2,3-dihydro-1H-isoindolin-1-one (2i).
4.7. (S)-3-Benzyl-2,3-dihydro-1H-isoindolin-1-one (2e).
Following general procedure, (S)-N-sulfinylimine 1 (80 mg,
0.3 mmol) and 0.5M etheral solution of p-tolylmagnesium
bromide (1.8 mL, 0.9 mmol) were reacted at 40 C for 90 min.
Following general procedure, (R)-N-sulfinylimine 1
(80mg, 0.3 mmol) and 2M etheral solution of benzylmagnesium
bromide (0.33 mL, 0.66 mmol) were reacted at 40 oC for 90 min.
Product was purified using column chromatography on silica gel
using acetone:hexane 1:3 (v/v) to give 48 mg of white crystals
(71%). The spectroscopic data matched those reported in the
literature:30 1H NMR (400 MHz, CDCl3) δ: 2.82 (dd, J = 8.7 Hz,
13.7 Hz, 1H, C3-CH2), 3.22 (dd, J = 5.4 Hz, 13.7 Hz, 1H, C3-
CH2), 4.80 (dd, J = 5.4 Hz, 8.7 Hz, 1H, C3-H), 6.75 (br, 1H, N-
H), 7.21-7.36 (m, 6H, Ar), 7.47 (t, J = 7.3 Hz, 1H, Ar), 7.55 (td, J
= 1.2 Hz, 7.5 Hz, 1H, Ar), 7.84 (d, J = 7.5 Hz, 1H, Ar). 13C NMR
(CDCl3) δ: 41.3, 57.9, 122.7, 123.8, 127.1, 128.3, 128.7, 129.2,
o
Product was purified using column chromatography on silica gel
using acetone:hexane 1:3 (v/v) to give 61 mg of white crystals
(90%). The spectroscopic data matched those reported in the
literature:33 1H NMR (400 MHz, CDCl3) δ: 2.34 (s, 3H, CH3),
5.59 (s, 1H, C3-H), 6.52 (br, 1H, N-H), 7.12-7.18 (m, 4H, Ar),
7.22 (d, J = 7.4 Hz, 1H, Ar), 7.43-7.53 (m, 2H, Ar), 7.88 (dd, J =
1.2 Hz, 6.6 Hz, 1H, Ar). 13C NMR (CDCl3) δ: 21.1, 60.5, 123.3,
123.8, 126.7, 128.3, 129.7, 130.7, 132.3, 135.3, 138.4, 148.1,
20
20
170.8. [α]D = -100.5 (c = 0.75, CH2Cl2). lit. [α]D =+29.2 (c =
1.0, CH2Cl2).33
20
131.6, 131.9, 136.8, 146.8, 170.4. [α]D = -53.4 (c = 0.5,
4.12. (S)-tert-Butyl-butyl sulfoxide (3c).

6
Tetrahedron
o
Following general procedure, (S)-N-sulfinylimine 1 (60 mg,
bromide (2.25 mL, 1.123 mmol) were reacted at 40 C for 30
min. Column chromatography on silica gel using acetone:hexane
1:3 (v/v) gave 71 mg of oil (96%). The spectroscopic data
matched those reported in the literature:40 1H NMR (400 MHz,
CDCl3) δ: 1.15 (s, 9H, t-Bu), 2.41 (s, 3H, CH3), 7.26-7.30 (m,
2H, Ar), 7.45-7.49 (m, 2H, Ar). 13C NMR (CDCl3) δ: 21.3, 22.6,
ACCEPTED MANUSCRIPT
0.225 mmol) and 2M etheral solution of n-butylmagnesium
bromide (0.34 mL, 0.674 mmol) were reacted at 0 oC for 90 min.
Column chromatography on silica gel using ethyl acetate:hexane
1:1 (v/v) gave 32 mg of oil (88%). The spectroscopic data
matched those reported in the literature:34 1H NMR (400 MHz,
CDCl3) δ: 0.95 (t, J = 7.3 Hz, 3H, CH3), 1.23 (s, 9H, t-Bu), 1.38-
1.59 (m, 2H, CH2), 1.67-1.90 (m, 2H, CH2), 2.38-2.49 (m, 2H,
CH2). 13C NMR (CDCl3) δ: 13.7, 22.2, 22.8, 25.7, 45.3, 52.6.
20
55.5, 126.1, 129.0, 136.6, 141.4. [α]D = -165.8 (c = 0.96,
20
CH2Cl2). Lit. [α]D = -144.9 (c = 0.046, EtOH) for (S)
enantiomer.40
20
[α]D = -97.9 (c = 1.25, CH2Cl2). Lit. [α]D = -129 (c = 1.02,
4.18. (R,SS)-N-tert-butylsulfinyl-3-isopropyl-2,3-dihydro-1H-
isoindolin-1-one (4).
acetone) for (S) enantiomer.34
4.13. (S)-Benzyl tert-butyl sulfoxide (3e).
Following general procedure, (S)-N-sulfinylimine 1 (100 mg,
0.374 mmol) and 2M solution of isopropylmagnesium chloride in
THF (0.468 mL, 0.936 mmol) were reacted at rt for 90 min.
Column chromatography on silica gel using ethyl acetate:hexane
1:1 (v/v) gave 52 mg of white crystals (50%); mp 127-130 oC. IR
(ATR): 1701, 1084, 1055, 745 cm-1. 1H NMR (400 MHz, CDCl3)
δ: 0.50 (d, J = 6.6 Hz, 3H, CH3), 1.19 (d, J = 7 Hz, 3H, CH3),
1.37 (s, 9H, t-Bu), 3.05 (dsep. J = 3.7 Hz, 7.0 Hz, 1H, C-H), 5.15
(d, J = 3.3 Hz, 1H, C3-H), 7,43-7.51 (m, 2H, Ar), 7.58 (td, J = 1.2
Hz, 7.4 Hz, 1H, Ar), 7.87 (d, J = 7.4 Hz, 1H, Ar). 13C NMR
(CDCl3) δ: 14.5, 19.5, 23.7, 30.7, 60.8, 68.1, 123.6, 124.7, 128.5,
130.4, 132.6, 144.5, 169.8. HRMS (ESI) m/z calcd for
C15H22NO2S (M+H)+ 280.1366, found: 280.1364. [α]D20 =+4.6 (c
=1.1, CH2Cl2).
Following general procedure, (S)-N-sulfinylimine 1 (100 mg,
0.374 mmol) and 2M etheral solution of benzylmagnesium
bromide (0.415 mL, 0.823 mmol) were reacted at 40 C for 90
min. Column chromatography on silica gel using acetone:hexane
1:3 (v/v) gave 58 mg of oil (79%). The spectroscopic data
matched those reported in the literature:35 1H NMR (400 MHz,
CDCl3) δ: 1.32 (s, 9H, t-Bu), 3.62 and 3.82 (AB, J = 12.8 Hz,
2H), 7.28-7.38 (m, 5H, Ar). 13C NMR (CDCl3) δ: 23.0, 52.8,
o
20
53.6, 127.9, 128.7, 129.9, 131.9. [α]D = -181.7 (c = 1.12,
CH2Cl2). Lit. [α]D = -191.1 (c = 1.0, CHCl3) for (S) enantiomer.36
4.14. (R)-tert-Butyl-phenyl sulfoxide (3f).
Following general procedure, (S)-N-sulfinylimine 1 (100 mg,
0.374 mmol) and 3M etheral solution of phenylmagnesium
bromide (0.374 mL, 1.122 mmol) were reacted at -20 C for 90
4.19. (S)-3-Methoxy-2,3-dihydro-1H-isoindolin-1-one (5).
o
To a solution of sodium methoxide in methanol (0.035M, 3
mL, 0.1 mmol) was added (S)-N-sulfinylimine 1 (50 mg, 0.187
mmol) at rt. The solution was left overnight at rt. Methanol was
evaporated. Sat. NH4Cl solution was added to the residue and the
aqueous layer was extracted with CH2Cl2 (3 x 5 mL). The
combined organic layers were dried over MgSO4, filtered, and
evaporated. White crystals were washed with hexane and dried
under vacuum. Yield 31 mg (46%). The spectroscopic data
matched those reported in the literature:41 1H NMR (400 MHz,
CDCl3) δ: 3.15 (s, 3H, OCH3), 6.00 (d, J = 0.8 Hz, 1H, C3-H),
6.37 (br, 1H, N-H), 7.52-7.58 (m, 2H, Ar), 7.61-7.65 (m, 1H,
Ar), 7.83-7.86 (m, 1H, Ar). 13C NMR (CDCl3) δ: 51.8, 84.5,
min. Column chromatography on silica gel using acetone:hexane
1:3 (v/v) gave 38 mg of oil (56%). The spectroscopic data
matched those reported in the literature:37 1H NMR (400 MHz,
CDCl3) δ: 1.15 (s, 9H. t-Bu), 7.43-7.50 (m, 3H, Ar), 7.55-7.60
(m, 2H, Ar). 13C NMR (CDCl3) δ: 22.7, 55.7, 126.2, 128.3,
20
22
131.1, 139.9. [α]D = +152.3 (c = 0.96, CH2Cl2). Lit. [α]D
=
+174.6 (c = 1.0, CHCl3) for (R) enantiomer.37
4.15. (R)-tert-Butyl-2-methoxyphenyl sulfoxide (3g).
Following general procedure, (S)-N-sulfinylimine 1 (50 mg,
0.288 mmol) and 1M etheral solution of o-
methoxyphenylmagnesium bromide (0.56 mL, 0.561 mmol) were
o
123.6, 123.7, 129.9, 132.1, 132.5, 142.7, 170.6. HRMS (ESI) m/z
reacted at 20 C for 90 min. Column chromatography on silica
calcd for C9H9NO2 (M+H)+ 164.0705, found: 164.0706. [α]D
=
20
gel using ethyl acetate:hexane 1:1 (v/v) gave 38 mg of yellow
crystals (95%). The spectroscopic data matched those reported in
the literature:38 1H NMR (400 MHz, CDCl3) δ: 1.19 (s, 9H, t-Bu),
3.83 (s, 3H, OCH3), 6.90 (d, J = 8.1 Hz, 1H, Ar), 7.13 (t, J = 7.5
Hz, 1H, Ar), 7.42 (t, J = 8.1 Hz, 1H, Ar), 7.75 (dd, J = 1.4 Hz, 7.7
Hz, 1H, Ar). 13C NMR (CDCl3) δ: 22.8, 55.4, 57.3, 110.6, 120.9,
+78.1 (c = 0.88, CH2Cl2).
Hexane washings contained methyl tert-butanesulfinate. The
spectroscopic data matched those reported in the literature.42 1H
NMR (400 MHz, CDCl3) δ: 1.18 (s, 9H, t-Bu), 3.80 (s, 3H,
OCH3).
20
127.3, 128.5, 132.2, 157.0. [α]D = +262.8 (c = 1.05, CH2Cl2).
Lit. [α]D = +281.9 (c = 1.0, EtOH) for (R) enantiomer.38
4.16. (S)-para-Chlorophenyl-tert-butyl sulfoxide (3h).
4.20. 3-Methylene-2,3-dihydro-1H-isoindolin-1-one (6).
To the solution of dimethylsulfoxide (64 mg, 0.82 mmol) in
THF (4 mL) was added butyllithium solution in hexane (2.5M,
0.3 mL, 0.748 mmol) at -30 oC. Resulting mixture was stirred at -
Following general procedure, (R)-N-sulfinylimine 1 (100 mg,
o
0.374
mmol)
and
1M
etheral
solution
of
p-
30 C for 30 min and the solution of (R)-N-sulfinylimine 1 (50
chlorophenylmagnesium bromide (1.123 mL, 1.123 mmol) were
mg, 0.187 mmol) in THF (2 mL) was added dropwise. Stirring
was continued for 90 min while the reaction mixture was warmed
slowly to rt. Sat. NH4Cl solution was added and the aqueous
layer was extracted with ethyl acetate (2 x 5 mL) and CH2Cl2 (1 x
5 mL). The combined organic layers were dried over MgSO4,
filtered, and evaporated. Product was purified using column
chromatography on silica gel AcOEt:Hexane 2:1 (v/v). Yield 24
mg of yellow crystals (44%). The spectroscopic data matched
those reported in the literature:43 1H NMR (400 MHz, CDCl3) δ:
5.01 (d, J = 2.0 Hz, 1H, =CH), 5.22 (d, J = 2.0 Hz, 1 H, =CH),
7.52 (td, J = 0.8 Hz, 7.4 Hz, 1H, Ar), 7.62 (td, 0.8 Hz, 7.4 Hz,
1H, Ar), 7.71 (d, J = 7.4 Hz, 1H, Ar), 7.86 (d, J = 7.8 Hz, 1H,
o
reacted at 40 C for 20 min. Column chromatography on silica
gel using acetone:hexane 1:3 (v/v) gave 77 mg of oil (95%).
Analogously was obtained second enantiomer. The spectroscopic
data matched those reported in the literature:39 1H NMR (400
MHz, CDCl3) δ: 1.12 (s, 9H, t-Bu), 7.41-7.45 (m, 2H, Ar), 7.47-
7.51 (m, 2H, Ar). 13C NMR (CDCl3) δ: 22.6, 55.9, 127.5, 128.6,
137.3, 138.4. [α]D20 = -146.9 (c = 1.05, CH2Cl2).
4.17. (S)-tert-Butyl-p-tolyl sulfoxide (3i).
Following general procedure, (R)-N-sulfinylimine 1 (100 mg,
0.374 mmol) and 0.5 M etheral solution of p-tolylmagnesium

7
Ar), 8.72 (br, 1H, N-H). 13C NMR (CDCl3) δ: 90.8, 120.2, 123.3,
129.5, 130.0, 132.2, 137.1, 139.8, 169.1.
3. Lippmann, W. US 4,267,189, 1981.
ACCEPTED MANUSCRIPT
4. Hardcastle, I. R.; Liu, J. F.; Valeur, E.; Watson, A.; Ahmed, S. U.;
Blackburn, T. J.; Bennaceur, K.; Clegg, W.; Drummond, C.;
Endicott, J. A.; Golding, B. T.; Griffin, R. J.; Gruber, J.; Haggerty,
K.; Harrington, R. W.; Hutton, C.; Kemp, S.; Lu, X. C.;
McDonnell, J. M.; Newell, D. R.; Noble, M. E. M.; Payne, S. L.;
Revill, C. H.; Riedinger, C.; Xu, Q.; Lunec, J. J. Med. Chem.
2011, 54, 1233-1243.
5. Wrobel, J.; Dietrich, A.; Woolson, S. A.; Millen, J.; McCaleb, M.;
Harrison, M. C.; Hohman, T. C.; Sredy, J.; Sullivan, D. J. Med.
Chem. 1992, 35, 4613-4627.
6. De Clercq, E., J. Med. Chem. 1995, 38, 2491-2517.
7. Volpe, R.; Mautner, L. S., Appl. Ther. 1961, 3, 521-528.
8. Bernstein, P. R.; Aharony, D.; Albert, J. S.; Andisik, D.; Barthlow,
H. G.; Bialecki, R.; Davenport, T.; Dedinas, R. F.; Dembofsky, B.
T.; Koether, G.; Kosmider, B. J.; Kirkland, K.; Ohnmacht, C. J.;
Potts, W.; Rumsey, W. L.; Shen, L. H.; Shenvi, A.; Sherwood, S.;
Stollman, D.; Russell, K. Bioorg. Med. Chem. Lett. 2001, 11,
2769-2773.
4.21. Reaction of lithium dibutyl phosphonate with N-
sulfinylimine 1.
To the solution of dibutyl phosphonate (99 mg, 0.722 mmol)
in diethyl ether (2 mL) was added dropwise n-butyllithium
solution in hexane (2.5M, 0.28 mL, 0.70 mmol) at 0 oC. After 15
min a solution of (S)-N-sulfinylimine 1 (62 mg, 0.23 mmol) in
diethyl ether (3 mL) was added. The reaction mixture was stirred
o
at 0 C for 2 hrs and quenched with sat. NH4Cl solution. The
resulting mixture was then extracted with CH2Cl2 (3 × 5 mL).
The combined organic layers were dried over MgSO4, filtered,
and evaporated. The obtained crystals of phthalimide 7 were
washed with ether- hexane 1:1 (v/v) mixture. Yield 9 mg (16%).
The spectroscopic data matched those reported in the literature:44
1H NMR (400 MHz, CDCl3) δ: 7.74-7.79 (m, 2H, Ar), 7.85-7.92
(m, 2H, Ar).
9. Zhuang, Z. P.; Kung, M. P.; Mu, M.; Kung, H. F. J. Med. Chem.
1998, 41, 157-166.
10. Kulkarni, S. K.; Ninan, I. Fundam. Clin. Pharmacol. 2000, 14,
529-539.
The washings were evaporated and purified using column
chromatography on silica gel AcOEt:Hexane 1:2.3 (v.v) to give
O,O-dibutyl-S-t-butyl phosphorothioate 8 (oil) 55 mg (90%). IR
11. (a) Chen, M. D.; Zhou, X.; He, M. Z.; Ruan, Y. P.; Huang, P. Q.
Tetrahedron 2004, 60, 1651-1657; (b) Deniau, E.; Couture, A.;
Grandclaudon, P. Tetrahedron: Asymmetry 2008, 19, 2735-2740.
12. Li, T. T.; Zhou, S. B.; Wang, J.; Acena, J. L.; Soloshonok, V. A.;
Liu, H. Chem. Commun. 2015, 51, 1624-1626.
1
(ATR): 1251, 1020, 976, 610 cm-1. H NMR (400 MHz, CDCl3)
δ: 0.92 (t, J = 7.3 Hz, 6H), 1.34-1.45 (m, 4H), 1.53 (d, J = 1.3 Hz,
9H), 1.62-1.70 (m, 4H), 3.98-4.14 (m, 4H). 13C NMR (CDCl3) δ:
13.6, 18.7, 32.2 (J = 7.1 Hz), 32.7 (J = 6.4 Hz), 49.8 (J = 4.5 Hz),
67.0 (J = 7.1 Hz). 31P NMR (CDCl3) δ: 25.3. HRMS (ESI) m/z
calcd for C12H28O3PS (M+H)+ 283.1491, found: 283.1488.
13. Lamblin, M.; Couture, A.; Deniau, E.; Grandclaudon, P.
Tetrahedron: Asymmetry 2008, 19, 111-123.
14. Comins, D. L.; Schilling, S.; Zhang, Y. C. Org. Lett. 2005, 7, 95-
98.
15. Fujioka, M.; Morimoto, T.; Tsumagari, T.; Tanimoto, H.;
Nishiyama, Y.; Kakiuchi, K. J. Org. Chem. 2012, 77, 2911-2923.
16. Suzuki, Y.; Kanai, M.; Matsunaga, S., Chem. Eur. J. 2012, 18,
7654-7657.
4.22. Dibutyl 2,3-dihydro-1H-isoindolin-1-one-3-phosphonate
(9).
17. Bisai, V.; Unhale, R. A.; Suneja, A.; Dhanasekaran, S.; Singh, V.
K. Org. Lett. 2015, 17, 2102-2105.
To a solution of (S)-N-sulfinylimine 1 (50 mg, 0.187 mmol)
and dibutyl phosphonate (77 mg, 0.562 mmol) in dry
dichloromethane (3 mL) was added K2CO3 (130 mg, 0.935
mmol). The reaction mixture was stirred for 24 h. Precipitate was
centrifuged and the solution was evaporated. The residue was
dissolved in ethanolic 4M HCl solution (0.1 mL) and the mixture
was left for 24 h. The solution was made alkaline with sat.
NaHCO3 solution and extracted with dichloromethane (3 x 5
mL). Organic extracts were dried with MgSO4, filtered and
evaporated. Product was purified using column chromatography
on silica gel AcOEt:Hexane 3:1 v/v). 42 mg (70%) of white
18. Sallio, R.; Lebrun, S.; Schifano-Faux, N.; Goossens, J. F.;
Agbossou-Niedercorn, F.; Deniau, E.; Michon, C. Synlett 2013,
24, 1785-1790.
19. Di Mola, A.; Palombi, L.; Massa, A. An overview on asymmetric
synthesis of 3-substituted indolinones. In Targets in Heterocyclic
Systems: Chemistry and Properties; Attanasi, O. A.; Noto, R.;
Spinelli, D., Eds.; Italian Society of Chemistry: Rome, 2014; 18,
113-140.
20. (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984-995. (b) Robak, M. T.; Herbage, M. A.; Ellman, J. A.
Chem. Rev. 2010, 110, 3600-3740.
21. Sun, X. W.; Liu, M.; Xu, M. H.; Lin, G. Q. Org. Lett. 2008, 10,
1259-1262.
1
crystals. IR (ATR): 3219, 1694, 1657, 991 cm-1. H NMR (400
22. Fernandez-Salas, J. A.; Rodriguez-Fernandez, M. M.; Maestro, M.
C.; Garcia-Ruano, J. L. Eur. J. Org. Chem. 2014, 5265-5272.
23. Huang, Z.; Zhang, M.; Wang, Y.; Qin, Y. Synlett 2005, 1334-
1336.
24. Cainelli, G.; Giacomini, D.; Galletti, P., Eur. J. Org. Chem. 1999,
61-65.
MHz, CDCl3) δ: 0.80 (t, J = 7.4 Hz, 3H, CH3), 0.89 (t, J = 7.4 Hz,
3H, CH3), 1.13-1.43 (m, 6H, CH2x3), 1.55-1.64 (m, 2H, CH2),
3.64-3.73 (m, 1H, O-CH), 3.86-3.95 (m, 1H, O-CH), 4.02-4.15
(m, 2H, O-CH2), 4.95 (d, J = 13.6 Hz, 1H, C3-H), 6.62 (br, 1H,
N-H), 7.54 (t, J = 7.4 Hz, 1H, Ar), 7.62 (td, J = 1.2 Hz, 7.4 Hz,
1H, Ar), 7.73-7.77 (m, 1H, Ar), 7.89 (dd, J = 0.8 Hz, 7.4 Hz, 1H,
Ar). 13C NMR (CDCl3) δ: 13.4 (J = 7.1 Hz), 18.5 (J = 13.5 Hz),
32.2 and 32.4 (J = 5.6 Hz), 54.1 (J = 156.0 Hz), 67.0 and 67.5 (J
= 7.1 Hz), 124.0 (J = 1.1 Hz), 124.1 (J = 2.6 Hz), 128.8 (J = 2.2
Hz), 131.7 (J = 4.9 Hz), 132.1 (J = 2.6 Hz), 140.1 (J = 6.4 Hz),
170.7 (J = 3.0 Hz). 31P NMR (CDCl3) δ: 14.0. HRMS (ESI) m/z
calcd for C16H25NO4P (M+H)+ 326.1516, found: 326.1515.
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Acknowledgments
This work was supported by the National Science Centre in
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