Synthesis of Sulfonylated Lactams by Copper-Mediated Aminosulfonylation of 2-Vinylbenzamides with Sodium Sulfinates

Article abstract of DOI:10.1021/acs.joc.8b03002

Treatment of 2-vinylbenzamide derivatives with sulfinate sodium in the presence of Cu(NO₃)₂·3H₂O led to an intra/intermolecular aminosulfonylation reaction to produce sulfonylated lactams in moderate to good yields. The developed method features the easily available and stable sulfone reagents, ease of operation, and a broad functional group tolerance.

Full text of DOI:10.1021/acs.joc.8b03002

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Note
Synthesis of Sulfonylated Lactams by Copper-Mediated
Aminosulfonylation of 2-Vinylbenzamides with Sodium Sulfinates
Li-Jing Wang, Jia-Min Chen, Wei Dong, Cong-Ying Hou, Mingming
Pang, Wen-Bo Jin, Fu-Gui Dong, Zhi-Dong Xu, and Wei Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03002 • Publication Date (Web): 22 Jan 2019
Downloaded from http://pubs.acs.org on January 22, 2019
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Synthesis of Sulfonylated Lactams by Copper-Mediated
Aminosulfonylation of 2-Vinylbenzamides with Sodium Sulfinates
Li-Jing Wang*, [a, b] Jia-Min Chen, [a] Wei Dong, [a] Cong-Ying Hou, [a] Mingming
Pang, [a] Wen-Bo Jin, [a] Fu-Gui Dong, [a] Zhi-Dong Xu, [a, c] and Wei Li* [a, b]
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[a]
College of Chemistry & Environmental Science, Hebei University, 180 Wusi
Donglu, Baoding 071002, P. R. China.
[b] Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry
of Education, Key Laboratory of Chemical Biology of Hebei Province, Hebei
University, 180 Wusi Donglu, Baoding 071002, P. R. China.
[c] School of Chemical and Pharmaceutical Engineering, Hebei University of Science
& Technology, Shijiazhuang 050018, P. R. China.
E-mail: wanglj@hbu.edu.cn, liweihebeilab@163.com
ABSTRACT
O
O
Cu(NO3)2 3H2O, DMAP
R2
N O
OR2
R3SO2Na
R1
N
R1
H
℃
CH3NO2, Ar, 70
SO2R3
Treatment of 2-vinylbenzamide derivatives with sulfinate sodiums in the
presence of Cu(NO3)2·3H2O led to an intra-/intermolecular aminosulfonylation
reaction to produce sulfonylated lactams in moderate to good yields. The developed
method features the easily available and stable sulfone reagents, the ease of operation,
and a broad functional group tolerance.
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Sulfonylated compounds play a significant role in organic chemistry. Because
they are found to be a key structural motif in a diversity of drug molecules, bioactive
natural products, and organic materials.1 More importantly, sulfones are also versatile
synthons in organic transformations.2-3 As a consequence, the efficient synthesis of
sulfonylated compounds is of significant interest to the chemists and pharmacologists.
In recent years, the sulfonyl cascade/difunctionalization of unsaturated compounds
has been widely developed in the synthesis of organic sulfones.4 To date, two general
methodologies have been established, including intermolecular multi-component
difunctionalization of simple alkenes and alkynes,5 and intra-/intermolecular tandem
cyclization of unsaturated compounds.6 However, among them the direct
aminosulfonylations are limited, despite the fact that the frequent appearances of
amino and sulfone groups in pharmaceuticals and natural products.7 Furthermore, the
majority of the known aminosulfonylation literatures have focused on cascade
aminosulfonylation of alkynes.8 While the related aminosulfonylation of alkenes has
been less explored. Very recently, the Zhang group realized a copper-catalyzed azido
sulfonylation reactions of alkenes with sodium sulfinates, producing β-azidosulfonate
derivatives (Scheme 1a).9 Besides, the Wu group reported a four-component reaction
of 2-vinylbenzoic acids, aryldiazonium tetrafluoroborates, sulfur dioxide surrogate of
DABCO·(SO2)2, and nitriles, which was promoted by photocatalysis in the presence
of visible light, leading to sulfonated 1-isoindolinones (Scheme 1b).10 As part of our
continuing interest in sulfonylation reactions11 and nitrogen-containing heterocycles
synthesis,12 herein, we report an efficient and general method for the rapid synthesis
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of numerous sulfonylated lactams by using 2-vinylbenzamides and sulfinate sodiums
as the starting material and Cu(NO3)2·3H2O as the promoter in a one-pot manner
(Scheme 1c). This reaction provides a complementary strategy to the
aminosulfonylation of alkenes.
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Scheme 1. Aminosulfonylation of alkenes.
Zhang's work:
R2
N3
SO2R1
[Cu], TBPB
R1SO2Na
TMSN3
a)
R2
R3
R3
Wu's work:
Ar N2BF4
O
[Ru], BF3.OEt2
blue LED
O
COOH
b)
R1
N
DABCO.(SO2)2
R2 CN
R2
SO2Ar
This work:
O
O
R2
O
OR2
[Cu], DMAP
CH3NO2
c)
R1
R3SO2Na
N
N
R1
H
SO2R3
R3 = Aryl, Alkyl
Our study began with the intra-/intermolecular aminosulfonylation reaction of
N-methoxy-2-vinylbenzamide 1a with readily available sodium p-toluenesulfinate 2a
in the company of a CuII salt. It was found that the sulfonated 1-isoindolinone 3a was
obtained in 30% yield when the reaction was performed in the presence of Cu(OAc)2
in 3 mL of DCE at 50 °C (Table 1, entry 1). And the structure of 3a was
unambiguously confirmed by X-ray crystallographic analysis (see Supporting
Information). Subsequent survey on a range of copper salts indicated that
Cu(NO3)2·3H2O gave the best result (entries 2-4). Different solvents were also
investigated, and CH3NO2 was found to be the most efficient one (45%) among
CH3CN and THF (entries 5-7). We then turned to additives for a trial: DMAP, Et3N,
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DBU, 2,2'-Bipyridine, NaOAc, K2CO3, and KF were all effective for this reaction,
and the yield could be improved to 56% by using 2.0 equiv of DMAP (entries 8-14).
Encouraged by the above result, we continued to examine the effect of temperature,
pleasingly, the yield of 3a was improved to 64% at 70 °C (entries 15-17).
Additionally, we studied the loading of Cu(NO3)2·3H2O on the reaction, but there
were no better yields (entries 18 and 19). Furthermore, the loading of DMAP was
evaluated as well (entries 20-22). To our delight, the yield could be further increased
to 74% when using 3.0 equiv. of DMAP (entry 21). Then, the screening of the loading
of 2a indicated that 2.0 equiv. of 2a is still the best choice for this transformation
(entries 23 and 24). Control experiments with air were investigated as well (entries
25-26). The yield was reduced to 55% when the reaction was carried out under an air
atmosphere (entry 25). And the reaction didn’t work when we reduced
Cu(NO3)2·3H2O to 0.2 equiv under the above conditions (entry 26). Furthermore, in
order to avoid the high loading of copper salts, we want to test whether we can realize
this aminosulfonylation reaction efficiently in a catalytic way by introducing
oxidizing agents such as K2S2O8, SelectFluour and PhI(OAc)2, but regretfully they
were not suitable in this transformation (entries 27-29).
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Table 1. Screening of the reaction conditions.a
O
O
N OMe
SO2Na
Cu(NO3)2 3H2O, DMAP
OMe
N
O
S
H
℃
CH3NO2, Ar, 70 , 17h
O
1a
2a
3a
Entry Solvent
[Cu] (2.0 equiv)
Cu(OAc)2
Additives (equiv)
-
3a Yield (%)
T(℃)
1
DCE
50
30
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2
3
DCE
Cu(ClO4)2·6H2O
-
-
50
50
50
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50
50
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50
50
60
70
80
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23
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45
26
38
56
49
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62
64
60
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64
52
74
70
64
72
55
-
DCE
Cu(2-ethylhexanoate)2
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
4
DCE
-
5
CH3NO2
CH3CN
THF
-
6
-
7
-
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8
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
DMAP (2.0)
Et3N (2.0)
DBU (2.0)
2,2'-Bipyridine (2.0)
NaOAc (2.0)
K2CO3 (2.0)
KF (2.0)
9
10
11
12
13
14
15
16
17
18b
19c
20
21
22
23d
24e
25f
DMAP (2.0)
DMAP (2.0)
DMAP (2.0)
DMAP (2.0)
DMAP (2.0)
DMAP (1.0)
DMAP (3.0)
DMAP (3.5)
DMAP (3.0)
DMAP (3.0)
DMAP (3.0)
DMAP (3.0)
DMAP (3.0), K2S2O8
(2.0)
26f ,g CH3NO2
27g
28g
29g
CH3NO2
CH3NO2
CH3NO2
18
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
DMAP (3.0), SelectFluour
(2.0)
70
70
42
-
DMAP (3.0), PhI(OAc)2
(2.0)
a Reaction conditions: a mixture of 1a (0.2 mmol), 2a (2.0 equiv), copper salts (2.0 equiv), DMAP
b
(3.0 equiv) and CH3NO2 (3 mL) was stirred at 70 °C in schlenk tube under argon. 1.5 equiv of
Cu(NO3)2·3H2O was used. 3.0 equiv of Cu(NO3)2·3H2O was used. 1.5 equiv of 2a was used.e
c
d
f
g
3.0 equiv of 2a was used. Reaction was performed under air atmosphere. 0.2 equiv of
Cu(NO3)2·3H2O was used.
After establishing the above optimized condition, we explored the scope of this
aminosulfonylation, and the results are summarized in Scheme 2. First, compatibility
of the substitutions on the aryl group (1a-g) was explored. Substrates, including those
that were electron‐donating (1c-d), electron‐withdrawing (1e-g), or located at a
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sterically obstructing ortho position (1b), participated well in the reaction, affording
the aminosulfonylation products 3b-g in good yields. In addition, the
intra-/intermolecular cyclization could be smoothly carried out on a 1 mmol scale
without difficulty, as showed in the case of 3a. Then, unsaturated amide 1h was used
as the substrate, however, the reaction did not yield the expected 6-membered lactam
product 3h, and 1h was recovered in 23%. While unsaturated amide 1i was
decomposed and gave a messy result. We think that the carbon-carbon double bond
directly tethered to an aromatic ring is critical for the reactivity of the substrates. But
the details of the reason is still unclear. We continued to survey the structural effect of
the N-R2 moiety. Fortunately, 1j-l containing N-OR moiety all could afford the desired
products in good yields. But, the simple amides 1m was failed to produce the desired
product. Next, we shifted our attention to various sodium sulfinates to test the
synthetic potential of this method. As expected, sodium substituted benzenesulfinates
with a series of electronic properties operated well under the standard conditions and
produced compounds 3n-w in moderate to good yields. Moreover, sodium
2,4,6-trimethylbenzenesulfinate 2x and sodium naphthalene-2-sulfinate 2y could be
transformed into the corresponding products in 20% and 24% yields, respectively.
Notably, sodium alkanesulfinates were also suitable for this transformation. We can
get the aminosulfonylation compounds 3z-ac in good yields with them. Furthermore,
to expand the scope of this reaction, we also investigated substrate 1ad, but it was not
suitable for this transformation.
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Scheme 2. Scope of copper-mediated aminosulfonylation of 2-vinylbenzamides with
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sulfinate sodiums.a
6
7
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9
O
O
Cu(NO3)2 3H2O (2.0 equiv)
R2
DMAP (3.0 equiv)
R3SO2Na
N
R2
R1
N
R1
H
℃
CH3NO2, Ar, 70 , 17-48 h
SO2R3
2
3
1
10
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O
O
O
N
OMe
O
N
OMe
O
N
OMe
O
S
S
S
O
O
O
3b,
73%
3c,
68%
O
b
3a,
74% (58%)
O
O
Cl
MeO
N
OMe
O
N
OMe
O
N
OMe
O
Cl
S
S
S
O
O
O
3d,
47%
3f,
64%
3e,
55%
O
O
O
N
Ph
OMe
O
S
N
OCH3
O
OMe
O
N
F
S
S
O
O
O
3h
, 0%
3g,
60%
3i,
0%
O
O
N
O
OBn
O
N
OEt
O
N
OH
O
S
S
S
O
O
O
3j,
68%
3k,
3l,
63%
63%
O
O
N
O
OMe
O
N
Ph
O
N
OMe
O
R
S
S
S
R
O
O
O
3m,
0%
3n
3o
3p
3q
3r
(R = H, 64%)
3u
3v
3w
(R = CH3, 61%)
(R = Br, 34%)
(R = F, 47%)
(R = OMe, 58%)
t
O
(R = Bu, 50%)
(R = Cl, 61%)
(R = Br, 51%)
(R = F, 42%)
(R = Ph, 33%)
N
OMe
O
O
3s
3t
S
N
OMe
O
O
O
S
3x,
20%
S
O
O
O
3y,
24%
S
N
OMe
O
N
OMe
O
O
S
3aa,
52%
O
O
3z,
67%
N
OMe
O
N
O
O
OMe
O
3ab,
57%
OCH3
N
O
S
S
Ph
3ad,
O
O
38%
0%
3ac,
a Reaction conditions: a mixture of 1 (0.2 mmol), 2 (2.0 equiv), Cu(NO3)2·3H2O (2.0 equiv),
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DMAP (3.0 equiv) and CH3NO2 (3 mL) was stirred at 70 °C in schlenk tube under argon. b 1.0
mmol of 1a was used.
7
8
9
Scheme 3. Deprotection of N-methoxyamide 3a
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O
O
SmI2, THF, rt
N
OMe
O
NH
O
S
S
O
O
3a
4,
85%
To demonstrate synthetic utility of the products derived from this reaction, the
sulfonated 1-isoindolinone 3a was treated with SmI2, readily providing free lactam 4
in 85% yield (Scheme 3).
In order to shed some light on the mechanism of this transformation, several control
experiments were performed (Scheme 4). First, this transformation was terminated
and substrate 1a was recovered in 71% yield, when 2.0 equiv of TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxy) was added to the standard reaction. In addition,
the TEMPO trapped compound 5 was detected by ESI-HRMS measurements of the
crude reaction mixture (reaction 1 in Scheme 4). Next, when the reaction was carried
out in the presence of BHT (butylated hydroxytoluene, 2.0 equiv), the yield of 3a was
decreased to 43% and the BHT trapped product 6 and 7 were obtained in 8% and 18%
yields, respectively (reaction 2 in Scheme 4). Furthermore, when we tried to use
1,1-diphenylethylene (2.0 equiv) to trap the radical under the standard reaction
conditions, 3a was obtained in 51% yield and compound 8 could be detected by
ESI-HRMS measurements of the crude reaction mixture (reaction 3 in Scheme 4).
Together, these results clearly indicated that a radical pathway with C-centered radical
intermediate and sulfonyl radical intermediate may be involved in the above
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experiments.
6
7
8
9
Based on the above-mentioned experimental observations and literature
reports,12, 13 a plausible mechanism, containing two possible pathways, was proposed
as in Scheme 5. Initially, copper(II) salts coordinate with alkene 1a to form
intermediate A, which followed by the intramolecular aminocupration to afford
alkyl-copper intermediate B. The resulting complex B may undergo a reversible
homocleavage to generate C-centered radical intermediate C. Meanwhile, sodium
sulfinate 2a is oxidized by CuII to give sulfonyl radical D. In path a, intermediate B
couples with sulfonyl radical D to form intermediate E, which was followed by a
reductive elimination process to afford the corresponding product 3a and CuI. In path
b, the obtained radical intermediate C directly couples with sulfonyl radical D to
produce 3a.
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Scheme 4. Mechanistic studies
O
(1)
O
OMe
Cu(NO3)2 3H2O (2.0 equiv)
DMAP (3.0 equiv)
O
N
O
OMe
SO2Na
N
OMe
Ts
N
N
℃
CH3NO2, Ar, 70 , 17 h
H
TEMPO, 2.0 equiv
2a
, 2.0 equiv
3a,
1a,
0%
5
0.2 mmol
(by ESI-HRMS)
1a
was recovered in 71%
O
(2)
Cu(NO3)2 3H2O (2.0 equiv)
DMAP (3.0 equiv)
O
Ts
OMe
SO2Na
N
OMe
Ts
HO
N
H
℃
CH3NO2, Ar, 70 , 17 h
OTs
BHT, 2.0 equiv
2a
, 2.0 equiv
3a,
1a,
43%
0.2 mmol
6
, 8% (11.7 mg)
7
, 18% (28 mg)
O
(3)
O
Ts
Cu(NO3)2 3H2O (2.0 equiv)
DMAP (3.0 equiv)
OMe
N
OMe
Ts
SO2Na
N
H
Ph
Ph
Ph
Ph
8
(by ESI-HRMS)
℃
CH3NO2, Ar, 70 , 17 h
3a,
51%
2.0 equiv
2a
, 2.0 equiv
1a,
0.2 mmol
In summary, we have developed a new and practical copper-mediated alkene
aminosulfonylation reaction that is effective to access a variety of sulfonated lactams
in moderate to good yields. This reaction used easily available and stable sodium
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sulfinates as the ideal sulfone sources. Notably, this strategy represents an appealing
and complementary means to achieve alkene aminosulfonylation under mild reaction
conditions. Further studies of this strategy are currently underway in our laboratory.
Scheme 5. Plausible mechanism.
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O
O
O
O
OMe
OMe
N
N
H
N
OMe
CuII
N
OMe
CuI
CuII
A
C
B
1a
O
N
OMe
Ts
CuII
3a
3a
path a
path b
CuIII
E
CuI
O
O
S
O
S
S
O
O
O
D
Experimental Section
General Information. Reaction progress was monitored via thin layer
chromatography (TLC) performed on GF254 silica gel plates. Column
chromatography was carried out with silica gel (200-300 mesh). Unless stated
otherwise, all reactions were performed in schlenk tube and carried out under an
1
argon atmosphere. H NMR spectra were recorded on 600 or 400 MHz in CDCl3 or
13
DMSO-d6, C{H} NMR spectra were recorded on 150 or 100 MHz in CDCl3 or
19
DMSO-d6. F NMR spectra were recorded on 564 MHz in CDCl3. Chemical shifts
(ppm) were recorded with tetramethylsilane (TMS) as the internal reference standard.
Multiplicities are given as: s (singlet), d (doublet), t (triplet), dd (doublet of doublets),
dt (doublet of triplets) or m (multiplet). IR spectra were recorded on a FT-IR
spectrometer and only major peaks are reported in cm-1. Melting points were
determined on a microscopic apparatus and were uncorrected. Products 3, were
further characterized by high resolution MS (TLQ, Q-TOF or FTICR) (ESI ionization
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sources); copies of their 1H NMR， C NMR and 19F NMR spectra are provided in the
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Supporting Information. Commercial grade solvents and reagents were used without
further purification.
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Starting Materials. Substrates 113a, 14 and 211 was prepared according to
the literature.
Typical procedure for the preparation of product 3a. 3 mL CH3NO2 was added
to 1a (0.2 mmol, 35.4 mg), Tol-SO2Na 2a (0.4 mmol, 73.5mg), Cu(NO3)2·3H2O (0.4
mmol, 97.6 mg) and 3.0 equiv DMAP (0.6 mmol, 74.0 mg) under Argon. The mixture
was stirred for 17 h at 70 ℃. After the reaction finished as indicated by TLC, the
reaction mixture was concentrated in vacuo and purified by chromatography on silica
gel (elute: EtOAc/Petroleum ether 1/3, v/v) to give the desired product 3a (49.0 mg,
74%).
10 mL CH3NO2 was added to 1.0 mmol (177.0 mg) 1a, Tol-SO2Na 2a (2 mmol,
367.5 mg), Cu(NO3)2·3H2O (2 mmol, 488.0 mg) and 3.0 equiv DMAP (3 mmol,
370.0 mg) under Argon. The mixture was stirred for 36 h at 70 ℃. The 3a was
obtained in a yield of 58% (192.2 mg).
Characterization data of 1c,1f, 1i and 1j:
N-methoxy-4-methyl-2-vinylbenzamide 1c. 1H NMR (CDCl3, 600 MHz) δ 8.94 (s,
1H), 7.34 (s, 1H), 7.25 (t, J = 7.2Hz, 1H), 7.04 (m, 1H), 6.97 (m, 1H), 5.68 (dd, J =
18Hz, J = 3.6Hz, 1H), 5.30 (dd, J = 10.8Hz, J = 4.8Hz, 1H), 3.81 (s, 1H), 2.35 (d, J =
13
2.4Hz, 1H). C{H} NMR (CDCl3, 150 MHz) δ 167.2, 140.6, 136.3, 133.9, 128.7,
128.1, 127.7, 126.5, 116.3, 64.1, 21.2.
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5-chloro-N-methoxy-2-vinylbenzamide 1f. 1H NMR (CDCl3, 600 MHz) δ 8.87 (s,
1H), 7.49 (d, J = 9Hz, 1H), 7.37 (d, J = 6.6Hz, 2H), 6.92 (dd, J = 16.8Hz, J = 10.8Hz,
1H), 5.71 (d, J = 17.4Hz, 1H), 5.38 (d, J = 10.8Hz , 1H), 3.86 (s, 3H). 13C{H} NMR
(CDCl3, 150 MHz) δ 165.7, 134.9, 133.4, 132.8, 132.7, 130.8, 127.7, 127.6, 117.8,
64.6.
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N-(benzyloxy)-2-vinylbenzamide 1j. H NMR (CDCl3, 600 MHz) δ 8.63 (s, 1H),
7.51 (d, J = 7.8Hz, 1H), 7.41 (s, 2H), 7.37-7.34 (m, 4H), 7.28 (d, J = 7.2, 1H), 7.20 (t,
J = 7.8Hz, 1H), 6.89 (dd, J = 17.4Hz, J = 11.4Hz, 1H), 5.65 (d, J = 17.6Hz, 1H), 5.26
13
(d, J = 10.8Hz, 1H), 4.99 (s, 2H). C{H} NMR (CDCl3, 150 MHz) δ 167.0, 136.4,
135.1, 133.8, 131.6, 130.6, 129.2, 128.7, 128.5, 127.7, 127.5, 126.1, 117.0, 78.2.
N-ethoxy-2-vinylbenzamide 1k. 1H NMR (CDCl3, 600 MHz) δ 8.87 (s, 1H), 7.55 (d,
J = 7.8Hz 1H), 7.39 (t, J = 7.8Hz 1H), 7.35 (d, J = 7.8Hz, 1H), 7.23 (t, J = 7.8Hz, 1H),
6.98 (dd, J = 16.8Hz, J = 11.4Hz, 1H), 5.70 (d, J = 17.4Hz, 1H), 5.33 (d, J = 10.8Hz,
1H), 4.04 (d, J = 6.0Hz, 2H), 1.29 (s, 3H). 13C{H} NMR (CDCl3, 150 MHz) δ 167.1,
136.2, 133.7, 131.7, 130.4, 127.6, 127.3, 125.8, 116.6, 72.0, 13.3.
Characterization data of 3a-3g, 3j-l, 3n-3ac:
2-methoxy-3-(tosylmethyl)isoindolin-1-one 3a. Light yellow solid (49.0 mg, 74%).
mp 125-127 ℃. 1H NMR (CDCl3, 600 MHz) δ 7.78 (d, J = 8.6Hz 2H), 7.73 (d, J =
7.8Hz, 1H), 7.70 (d, J = 7.2Hz, 1H), 7.54 (dt, J = 7.2Hz, J = 1.2Hz, 1H), 7.43 (t, J =
7.8Hz 1H), 7.32 (d, J = 7.8Hz 2H), 5.15 (dd, J = 7.8Hz, J = 3.0Hz, 1H), 3.78 (dd, J =
14.4Hz, J = 2.4Hz, 1H), 3.74 (s, 3H), 3.28 (dd, J = 14.4Hz, J = 7.8Hz, 1H), 2.39 (s,
13
3H). C{H} NMR (CDCl3, 150 MHz) δ 164.2, 145.4, 140.6, 136.2, 132.8, 130.1,
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129.2, 129.1, 128.0, 124.1, 123.8, 63.6, 57.0, 53.5, 21.6. IR (neat, cm-1): 2935, 1719,
1317, 1151, 1087, 998, 906, 815, 747, 687, 650, 562, 511. HRMS (ESI-TLQ) m/z:
[M+H]+ Calcd for C17H17NO4S 332.0944, Found: 332.0951.
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2-methoxy-4-methyl-3-(tosylmethyl)isoindolin-1-one 3b. Light yellow solid (50.4
mg, 73%), mp 157-159 ℃. 1H NMR (CDCl3, 600 MHz) δ 7.63 (d, J = 8.4Hz, 2H),
7.57 (d, J = 8.4Hz, 1H), 7.32 (t, J = 7.8Hz, 1H), 7.26-7.24 (m, 3H), 5.23 (dd, J =
4.8Hz, J = 2.4Hz, 1H), 3.71 (s, 3H), 3.67 (dd, J = 15.6Hz, J = 2.4Hz, 1H), 3.59 (dd, J
= 15.6Hz, J = 5.4Hz, 1H), 2.37 (s, 3H), 2.31 (s, 3H). 13C{H} NMR (CDCl3, 150 MHz)
δ 164.9, 145.1, 137.9, 136.5, 134.3, 133.2, 129.9, 129.6, 129.4, 128.0, 121.5, 63.7,
56.2, 53.7, 21.6, 17.7. IR (neat, cm-1): 2937, 2246, 1716, 1597, 1316, 1150, 1131,
1086, 1036, 900, 815, 748, 528, 514. HRMS (ESI-TLQ) m/z: [M+H]+ Calcd for
C18H19NO4S 346.1102, Found: 346.1108.
2-methoxy-5-methyl-3-(tosylmethyl)isoindolin-1-one 3c. Light yellow solid (47.0
mg, 68%). mp 125-127 ℃. 1H NMR (CDCl3, 600 MHz) δ 7.78 (d, J = 8.4Hz, 2H),
7.61 (d, J = 7.8Hz, 1H), 7.39 (s, 1H), 7.33 (d, J = 8.4Hz, 2H), 7.22 (d, J = 7.8Hz, 1H),
5.09 (dd, J = 7.2Hz, J = 2.4Hz, 1H), 3.77 (dd, J = 15.0Hz, J = 2.4Hz, 1H), 3.72 (s,
13
3H), 3.29 (dd, J = 14.4Hz, J = 7.2Hz, 1H), 2.40 (s, 3H), 2.37 (s, 3H). C{H} NMR
(CDCl3, 150 MHz) δ 164.6, 145.4, 143.8, 140.9, 136.2, 130.1, 130.1, 128.1, 126.4,
124.3, 123.6, 63.5, 57.0, 53.5, 22.0, 21.6. IR (neat, cm-1): 2931, 2359, 2248, 1716,
1620, 1456, 1316, 1152, 1086, 760, 727, 553, 515. HRMS (ESI-TLQ) m/z: [M+H]+
Calcd for C18H20NO4S 346.1102, Found: 346.1108.
2,6-dimethoxy-3-(tosylmethyl)isoindolin-1-one 3d. white solid (33.97 mg, 47%).
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mp 153-155℃. H NMR (CDCl3, 600 MHz) δ 7.78 (d, J = 7.8Hz, 2H), 7.60 (d, J =
8.4Hz, 1H), 7.33 (d, J = 7.8Hz, 2H), 7.22 (d, J = 2.4Hz, 1H), 7.07 (dd, J = 8.4Hz, J =
2.4Hz, 1H), 5.11 (dd, J = 7.8Hz, J = 2.4Hz, 1H), 3.78 (s, 3H), 3.76 (d, J = 2.4Hz, 1H),
3.74 (s, 3H), 3.23 (dd, J = 14.4Hz, J = 7.8Hz, 1H), 2.40 (s, 3H). 13C{H} NMR (CDCl3,
150 MHz) δ 164.3, 160.6, 145.4, 136.3, 132.6, 130.5, 130.1, 128.0, 125.3, 120.6,
106.9, 63.6, 57.1, 55.7, 53.3, 21.6. IR (neat, cm-1): 2939, 2838, 2359, 1717, 1595,
1493, 1316, 1286, 1147, 1087, 1017, 765 555, 517. HRMS (ESI-TLQ) m/z: [M+H]+
Calcd for C18H19NO5S 362.1051, Found: 362.1057.
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5-chloro-2-methoxy-3-(tosylmethyl)isoindolin-1-one 3e. Light yellow solid
(40.2mg, 55%). mp 168-170 ℃. 1H NMR (DMSO-d6, 600 MHz) δ 7.67 (d, J = 7.8Hz,
1H), 7.56 (d, J = 7.8Hz, 2H), 7.51 (dd, J = 7.8Hz, J = 1.2Hz, 1H), 7.44 (s, 1H), 7.34
(d, J = 8.4Hz, 2H), 5.27 (t, J = 4.8Hz, 1H), 4.20 (dd, J = 15.6Hz, J = 3.6Hz, 1H), 4.04
(dd, J = 15.6Hz, J = 5.4Hz, 1H), 3.78 (s, 3H), 2.40 (s, 3H). 13C{H} NMR (DMSO-d6,
150 MHz) δ 162.4, 144.5, 141.3, 136.9, 136.6, 129.7, 129.0, 128.3, 127.5, 124.5,
124.2, 63.0, 54.0, 53.7, 21.0. IR (neat, cm-1): 2927, 2360, 2341, 1719, 1613, 1316,
1152, 1135, 1086, 761, 669, 515. HRMS (ESI-TLQ) m/z: [M+H]+ Calcd for
C17H16ClNO4S 366.0560, Found: 366.0561.
6-chloro-2-methoxy-3-(tosylmethyl)isoindolin-1-one 3f. Light yellow solid (46.8
mg, 64%). mp 114-115 ℃. 1H NMR (DMSO-d6, 600 MHz) δ 7.68 (d, J = 1.2Hz, 1H),
7.64 (d, J = 8.4Hz, 2H), 7.57-7.56 (m, 2H), 7.38 (d, J = 7.8Hz, 2H), 5.28 (dd, J =
5.4Hz, J = 4.2Hz, 1H), 4.14 (dd, J = 15.0Hz, J = 3.6Hz, 1H), 4.00 (dd, J = 15.6Hz, J
13
= 5.4Hz, 1H), 13.74 (s, 3H), 2.40 (s, 3H). C{H} NMR (DMSO-d6, 150 MHz) δ
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161.9, 144.5, 138.5, 136.6, 133.7, 132.0, 131.4, 129.7, 127.6, 125.9, 122.4, 63.0, 54.3,
53.9, 21.0. IR (neat, cm-1): 2926, 2360, 2342, 1718, 1596, 1316, 1151, 1087, 816, 762,
668, 515. HRMS (ESI-TLQ) m/z: [M+H]+ Calcd for C17H16ClNO4S 366.0560,
Found: 366.0561.
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5-fluoro-2-methoxy-3-(tosylmethyl)isoindolin-1-one 3g. Light yellow solid (42.0mg,
60%). mp 173-175 ℃.1H NMR (CDCl3, 400 MHz) δ 7.86 (d, J = 8.4Hz, 2H), 7.81
(dd, J = 8.4Hz, J = 5.2Hz, 1H), 7.52 (dd, J = 8.4Hz, J = 2.0Hz, 1H), 7.42 (d, J =
8.0Hz, 2H), 7.21 (td, J = 8.8Hz, J = 2.4Hz, 1H), 5.21 (dd, J = 8.0Hz, J = 2.0Hz, 1H),
3.87 (dd, J = 14.4Hz, J = 2.4Hz, 1H), 3.83 (s, 3H), 3.33 (dd, J = 14.4Hz, J = 8.4Hz,
13
1H), 2.48 (s, 3H). C{H} NMR (CDCl3, 100 MHz) δ 166.9, 164.4, 163.4, 145.7,
143.0, 142.9, 135.9, 130.2, 128.0, 126.1, 126.0, 125.1, 125.1, 117.2, 117.0, 112.2,
111.9, 63.7, 56.5, 53.4, 53.3, 21.6. 19F NMR (CDCl3, 564 MHz) δ -103.8. IR (neat,
cm-1): 2935, 1720, 1599, 1481, 1317, 1243, 1151, 1087, 763, 556. HRMS (ESI-
FTICR) m/z: [M+H]+ Calcd for C17H17FNO4S 350.0854 Found: 350.0857.
2-(benzyloxy)-3-(tosylmethyl)isoindolin-1-one 3j. Light yellow solid (55.4 mg,
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68%). mp 121-123 ℃. H NMR (CDCl3, 600 MHz) δ 7.74 (d, J = 7.8Hz, 1H),
7.70-7.68 (m, 3H), 7.50 (t, J = 7.2Hz, 1H), 7.41 (t, J = 7.2Hz, 1H), 7.30-7.28 (m, 4H),
7.25 (t, J = 3.6Hz, 3H), 5.03 (d, J = 10.8Hz, 1H), 4.94 (d, J = 10.2Hz, 1H), 4.86 (dd, J
= 8.4Hz, J = 1.8Hz, 1H), 3.57 (dd, J = 13.8Hz, J = 1.8Hz, 1H), 3.06 (dd, J = 14.4Hz,
J = 8.4Hz, 1H), 2.38 (s, 3H). 13C{H} NMR (CDCl3, 150 MHz) δ 164.9, 145.3, 140.9,
136.3, 134.6, 132.7, 130.1, 129.7, 1291, 129.1, 129.0, 128.6, 127.9, 124.2, 123.7, 78.0,
56.5, 54.9,21.6. IR (neat, cm-1): 3032, 1926, 2359, 1718, 1470, 1318, 1151, 1087, 748,
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700, 561, 511. HRMS (ESI-TLQ) m/z: [M+H]+ Calcd for C23H22NO4S 408.1258,
Found: 408.1264.
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2-ethoxy-3-(tosylmethyl)isoindolin-1-one 3k. Light yellow solid (43.5 mg, 63%),
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mp 91-93 ℃. H NMR (CDCl3, 600 MHz) δ 7..79 (d, J = 7.8Hz, 2H), 7.72 (dd, J =
12.0Hz t, J = 7.8Hz, 2H), 7.53 (t, J = 7.8Hz, 1H), 7.43 (t, J = 7.8Hz, 1H), 7.33 (d, J =
7.8Hz, 2H), 5.11 (dd, J = 7.8Hz t, J = 1.2Hz, 1H), 4.02-3.99 (m, 1H), 3.94-3.90 (m,
1H), 3.83 (dd, J = 14.4Hz t, J = 1.8Hz, 1H), 3.23 (dd, J = 14.4Hz t, J = 7.8Hz, 1H),
2.40 (s, 3H), 1.18 (t, J = 7.2Hz, 3H). 13C{H} NMR (CDCl3, 150 MHz) δ 164.2, 145.4,
140.8, 136.2, 132.7, 130.1, 129.2, 129.1, 128.0, 124.1, 123.7, 71.9, 56.7, 54.1, 21.6,
13.5. IR (neat, cm-1): 2981, 2930, 2359, 1718, 1470, 1318, 1151, 1087, 1019, 748,
566, 511. HRMS (ESI-TLQ) m/z: [M+H]+ Calcd for C18H19NO4S 346.1103, Found:
346.1108.
2-hydroxy-3-(tosylmethyl)isoindolin-1-one 3l. Light yellow solid (40.6mg, 63%).
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mp 148-150. H NMR (CDCl3, 400 MHz) δ 7.87 (dd, J = 8.4Hz, J = 2.0Hz, 3H),
7.75-7.71 (m, 1H), 7.67 (dd, J = 3.6Hz, J = 0.4Hz, 1H), 7.57 (t, J = 7.6Hz, 1H), 7.40
(d, J = 8.0Hz, 2H), 5.95 (dd, J = 7.2Hz, J = 4.4Hz, 1H), 3.69 (dd, J = 15.2Hz, J =
4.4Hz, 1H), 3.59 (dd, J = 15.2Hz, J = 7.6Hz, 1H), 2.47 (s, 3H). 13C{H} NMR (CDCl3,
100 MHz) δ 169.0, 147.0, 145.5, 136.0, 134.6, 130.1, 130.0, 128.3, 125.9, 125.4,
122.5, 60.5, 21.7. IR (neat, cm-1): 2926, 1770, 1598, 1467, 1316, 1304, 1289, 1142,
1061, 988, 743, 552. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H16NO4S
318.0970 Found: 318.0975.
2-methoxy-3-((phenylsulfonyl)methyl)isoindolin-1-one 3n. White solid (40.6 mg,
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64%), mp 130-132 ℃. 1H NMR (CDCl3, 600 MHz) δ 7.99 (d, J = 7.8Hz, 2H), 7.82 (d,
J = 7.2Hz, 1H), 7.77 (d, J = 7.8Hz, 1H), 7.72 (t, J = 7.8Hz, 1H), 7.64-7.61 (m, 3H),
7.51 (t, J = 7.8Hz,1H), 5.25 (dd, J = 7.2Hz, J = 3.0Hz, 1H), 3.89 (dd, J = 14.4Hz, J =
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3.0Hz, 1H), 3.81 (s, 3H), 3.39 (dd, J = 15.0Hz, J = 7.8Hz, 1H). C{H} NMR
(CDCl3, 150 MHz) δ 164.1, 140.5, 139.1, 134.3, 132.8, 129.6, 129.3, 129.2, 128.0,
124.0, 123.8, 63.6, 56.9, 53.4. IR (neat, cm-1): 3064, 2935, 2360, 1717, 1447, 1309,
1151, 1086, 998, 744, 687, 564, 523. HRMS (ESI-TLQ) m/z: [M+H]+ Calcd for
C16H15NO4S 318.0788, Found: 318.0795.
2-methoxy-3-(((4-methoxyphenyl)sulfonyl)methyl)isoindolin-1-one 3o. Light
yellow solid (40.3 mg, 58%). mp 135-137 ℃. 1H NMR (CDCl3, 600 MHz) δ 7.82 (d,
J = 9.0Hz, 2H), 7.72 (dd, J = 15.6Hz, J = 7.2Hz, 2H), 7.54 (t, J = 7.8Hz, 1H), 7.43 (t,
J = 7.8Hz, 1H), 6.98 (d, J = 9.0Hz, 2H), 5.15 (dd, J = 7.8Hz, J = 2.4Hz, 1H), 3.82 (s,
3H), 3.77 (dd, J = 15.0Hz, J = 3.0Hz, 1H), 3.75 (s, 3H), 3.28 (dd, J = 14.4Hz, J =
13
7.8Hz, 1H). C{H} NMR (CDCl3, 150 MHz) δ 164.2, 164.1, 140.6, 132.8, 130.5,
130.2, 129.2, 129.1, 124.1, 123.8, 114.7, 63.6, 57.1, 55.7, 53.6. IR (neat, cm-1): 2938,
2842, 2360, 1718, 1594, 1498, 1319, 1262, 1147, 1089, 748,565. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C17H17NO5S 348.0901, Found: 348.0900.
3-(((4-(tert-butyl)phenyl)sulfonyl)methyl)-2-methoxyisoindolin-1-one 3p. Light
yellow solid (37.3 mg, 50%). mp 142-143 ℃. 1H NMR (CDCl3, 600 MHz) δ 7.90 (d, J
= 8.4Hz, 2H), 7.82 (d, J = 7.8Hz, 1H), 7.75 (d, J = 7.8Hz, 1H), 7.63-7.59 (m, 3H),
7.51 (t, J = 7.8Hz, 1H), 5.24 (dd, J = 7.2Hz, d, J = 2.4Hz, 1H), 3.88 (dd, J = 15.0Hz, d,
J = 2.4Hz, 1H), 3.80 (s, 3H), 3.36 (dd, J = 15.0Hz, d, J = 7.8Hz, 1H), 1.36 (s, 9H).
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13C{H} NMR (CDCl3, 150 MHz) δ 164.2, 158.4, 140.6, 136.0, 132.8, 129.2, 129.1,
127.9, 126.6, 124.0, 123.8, 63.5, 56.9, 53.5, 35.3, 31.0. IR (neat, cm-1): 2963, 2360,
1718, 1471, 1318, 1293, 1155, 1108, 1085, 759, 574, 501. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C20H23NO4S 374.1423, Found: 374.1421.
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3-(((4-chlorophenyl)sulfonyl)methyl)-2-methoxyisoindolin-1-one 3q. Light yellow
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solid (42.9 mg, 61%). mp 161-162 ℃. H NMR (CDCl3, 600 MHz) δ 7.82 (d, J =
9.0Hz, 2H), 7.74 (d, J = 7.2Hz, 1H), 7.68 (d, J = 7.8Hz, 1H), 7.56-7.53 (m, 1H), 7.50
(d, J = 8.4Hz, 2H), 7.44 (t, J = 7.8Hz, 1H), 5.17(dd, J = 7.2Hz, J = 3.0Hz, 1H), 3.80
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(d, J = 3.0Hz, 1H), 3.78 (s, 3H), 3.34(dd, J = 15.0Hz, J = 7.8Hz, 1H). C{H} NMR
(CDCl3, 150 MHz) δ 164.2, 141.1, 140.2, 137.6, 132.8, 129.8, 129.5, 129.3, 129.2,
124.0, 123.9, 63.7, 57.0, 53.5. IR (neat, cm-1): 3088, 2926, 2854, 2360, 1717, 1472,
1319, 1154, 1088, 759, 737, 555, 524. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C16H14ClNO4S 352.0406, Found: 352.0405.
3-(((4-bromophenyl)sulfonyl)methyl)-2-methoxyisoindolin-1-one 3r. Light yellow
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solid (40.4mg, 51%). mp 158-160 ℃. H NMR (CDCl3, 600 MHz) δ 7.82 (d, J =
8.4Hz, 3H), 7.76-7.74 (m, 3H), 7.62 (t, J = 7.8Hz, 1H), 7.52 (t, J = 7.8Hz, 1H), 5.25
(dd, J = 7.2Hz, J = 2.4Hz, 1H), 3.87 (d, J = 3.0Hz, 1H), 3.85 (s, 3H), 3.41 (dd, J =
9.0Hz, J = 7.2Hz, 1H). 13C{H} NMR (CDCl3, 150 MHz) δ 164.2, 140.2, 138.2, 132.9,
129.7, 129.5, 129.4, 129.2, 123.9, 123.9, 63.7, 57.0, 53.5. IR (neat, cm-1): 3087, 2934,
2360, 1717, 1574, 1471, 1319, 1154, 1084, 1067, 1009, 753, 551. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C16H14BrNO4S 395.9901, Found: 395.9900.
3-(((4-fluorophenyl)sulfonyl)methyl)-2-methoxyisoindolin-1-one 3s. Light yellow
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solid (28.2 mg, 42%). mp 135-137 ℃. 1H NMR (CDCl3, 600 MHz) δ 7.01-7.98 (m,
2H), 7.83 (d, J = 7.2Hz, 1H), 7.78 (d, J = 7.8Hz, 1H), 7.63 (dt, J = 7.8Hz, J = 1.2Hz,
1H), 7.53 (t, J = 7.2Hz, 1H), 7.29 (t, J = 8.4Hz, 2H), 5.26 (dd, J = 7.2Hz, J = 2.4Hz,,
1H), 3.88(d, J = 2.4Hz, 1H), 3.86 (s, 3H), 3.41 (dd, J = 14.4Hz, J = 7.2Hz, 1H). 13C{H}
NMR (CDCl3, 150 MHz) δ 167.0, 165.3, 164.2, 140.3, 135.3, 132.9, 131.0, 131.0,
129.4, 129.2, 124.0, 123.9, 117.0, 116.9, 63.7, 57.1, 53.5. 19F NMR (CDCl3, 564 MHz)
δ -102.0. IR (neat, cm-1): 2936, 2360, 2342, 1717, 1590, 1494, 1319, 1149, 1086, 748,
562, 511. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H14FNO4S 336.0703, Found:
336.0700.
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3-(([1,1'-biphenyl]-4-ylsulfonyl)methyl)-2-methoxyisoindolin-1-one 3t. Light
yellow liquid (26.0 mg, 33%). 1H NMR (CDCl3, 600 MHz) δ 7.97 (d, J = 8.4Hz, 2H),
7.76 (d, J = 7.8Hz, 1H), 7.74-7.73 (m, 3H), 7.57-7.54 (m, 3H), 7.46-7.42 (m, 3H),
7.38 (t, J = 7.82Hz, 1H), 5.22 (dd, J = 7.2Hz, J = 2.4Hz, 1H), 3.85 (dd, J = 15.0Hz, J
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= 3.0Hz, 1H), 3.77 (s, 3H), 3.35 (dd, J = 14.4Hz, d, J = 7.8Hz, 1H). C{H} NMR
(CDCl3, 150 MHz) δ 164.2, 147.4, 140.6, 138.8, 137.6, 132.9, 129.3, 129.2, 129.2,
128.9, 128.6, 128.2, 127.4, 124.1, 123.9, 63.7, 57.1, 53.5. IR (neat, cm-1): 3056, 2928,
2360, 1717, 1471, 1314, 1150, 1124, 1072, 907, 750, 557. HRMS (ESI-FTICR) m/z:
[M+H]+ Calcd for C22H20NO4S 394.1113, Found: 394.1108.
2-methoxy-3-((m-tolylsulfonyl)methyl)isoindolin-1-one 3u. Light yellow solid
(40.4 mg, 61%), mp 119-121 ℃. 1H NMR (CDCl3, 600 MHz) δ 7.76 (d, J = 7.8Hz,
1H), 7.72 (d, J = 8.4Hz, 3H), 7.55 (dt, J = 7.2Hz, d, J = 1.2Hz, 1H), 7.46-7.41 (m,
3H), 5.18 (dd, J = 7.8Hz, J = 3.0Hz, 1H), 3.81 (dd, J = 14.4Hz, J = 2.4Hz, 1H), 3.75
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(s, 3H), 3.29 (dd, J = 15.0Hz, J = 7.8Hz, 1H), 2.40 (s, 3H). 13C{H} NMR (CDCl3, 150
MHz) δ 164.2, 140.6, 140.0, 139.0, 135.1, 132.9, 129.5, 129.3, 129.2, 128.3, 125.2,
124.1, 123.9, 63.6, 56.9, 53.5, 21.3. IR (neat, cm-1): 2926, 2360, 2342, 1717, 1742,
1457, 1318, 1302, 1145, 747, 685, 518. HRMS (ESI-TLQ) m/z: [M+H]+ Calcd for
C17H17NO4S 332.0944, Found: 332.0951.
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3-(((3-bromophenyl)sulfonyl)methyl)-2-methoxyisoindolin-1-one 3v. Light yellow
solid (26.9 mg, 34%). mp 138-139 ℃. 1H NMR (CDCl3, 600 MHz) δ 8.01 (s, 1H),
7.83 (d, J = 8.4Hz, 1H), 7.76 (d, J = 7.2Hz, 2H), 7.68 (d, J = 7.8Hz, 1H), 7.56 (t, J =
7.8Hz, 1H), 7.47-7.41 (m, 2H), 5.19 (dd, J = 7.2Hz, J = 3.0Hz, 1H), 3.82 (d, J =
3.0Hz, 1H), 3.79 (s, 3H), 3.36 (dd, J = 15.0Hz, J = 7.8Hz, 1H). 13C{H} NMR (CDCl3,
150 MHz) δ 164.2, 141.0, 140.2, 137.4, 132.9, 131.1, 131.0, 129.5, 129.2, 126.5,
124.0, 123.6, 63.7, 57.0, 53.4. IR (neat, cm-1): 2925, 2854, 2360, 1717, 1471, 1458,
1319, 1295, 1153, 736, 678, 525. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C16H14BrNO4S 395.9901, Found: 395.9900.
3-(((3-fluorophenyl)sulfonyl)methyl)-2-methoxyisoindolin-1-one 3w. Light yellow
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solid (31.5 mg, 47%). mp 123-125 ℃. H NMR (CDCl3, 600 MHz) δ 7.75 (d, J =
7.8Hz, 1H), 7.69 (t, J = 7.8Hz, 2H), 7.60-7.59 (m, 1H), 7.56-7.52 (m, 2H), 7.45 (t, J =
7.8Hz, 1H), 7.34 (dt, J = 7.8Hz, J = 2.4Hz, 1H), 5.19 (dd, J = 7.2Hz, J = 3.0Hz, 1H),
3.81 (dd, J = 15.0Hz, J = 3.0Hz, 1H), 3.78 (s, 3H), 3.35 (dd, J = 14.4Hz, J = 7.2Hz,
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1H). C{H} NMR (CDCl3, 150 MHz) δ 164.2, 163.4, 161.7, 141.2, 141.2, 140.2,
132.9, 131.5, 131.5,129.4, 129.2, 124.0, 123.9, 123.8, 123.8, 121.7, 121.5, 115.5,
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115.3, 63.7, 56.9, 53.4. F NMR (CDCl3, 564 MHz) δ -108.2. IR (neat, cm-1): 3074,
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2926, 2360, 1717, 1472, 1436, 1322, 1305, 1225, 1131, 747, 678, 529. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C16H14FNO4S 336.0703, Found: 336.0700.
3-((mesitylsulfonyl)methyl)-2-methoxyisoindolin-1-one 3x. Light yellow solid
(14.4 mg, 20%). mp 116-118 ℃. 1H NMR (CDCl3, 600 MHz) δ 7.86 (dd, J = 18.0Hz,
J = 7.8Hz, 2H), 7.64 (dt, J = 7.8Hz, J = 0.6Hz 1H), 7.53-7.51 (m, 1H), 7.01 (s, 2H),
5.33 (dd, J = 7.8Hz, J = 2.4Hz, 1H), 3.93 (t, J = 3.0Hz, 1H), 3.86 (s, 3H), 3.31 (dd, J
= 14.4Hz, J = 7.8Hz, 1H), 2.71 (s, 6H), 2.33 (s, 3H). 13C{H} NMR (CDCl3, 150 MHz)
δ 164.1, 144.1, 141.1, 140.0, 132.9, 132.9, 132.5, 129.2, 129.1, 124.1, 123.9, 63.6,
56.5, 52.9, 22.9, 21.0. IR (neat, cm-1): 2925, 2854, 2360, 1717, 1558, 1457, 1313,
1148, 748, 646, 578, 517. HRMS (ESI-TLQ) m/z: [M+H]+ Calcd for C19H21NO4S
360.1256, Found: 360.1264.
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2-methoxy-3-((naphthalen-2-ylsulfonyl)methyl)isoindolin-1-one 3y. Light yellow
solid (17.6 mg, 24%). mp 127-128 ℃.1H NMR (CDCl3, 600 MHz) δ 8.6 (s, 1H), 8.06
(d, J = 9.0Hz, 1H), 8.01 (d, J = 8.4Hz, 1H), 7.96 (d, J = 8.4Hz, 1H), 7.93 (dd, J =
8.4Hz, J = 1.8Hz, 1H), 7.82 (d, J = 7.8Hz, 2H), 7.72 (t, J = 7.8Hz, 1H), 7.67 (t, J =
7.8Hz, 1H), 7.61 (t, J = 7.8Hz, 1H), 7.50 (t, J = 7.8Hz, 1H), 5.30 (dd, J = 7.2Hz, J =
2.4Hz, 1H), 3.97 (dd, J = 14.4Hz, J = 2.4Hz, 1H), 3.76 (s, 3H), 3.46 (d, J = 15.0Hz, J
= 7.8Hz, 1H). 13C{H} NMR (CDCl3, 150 MHz) δ 164.2, 140.6, 135.9, 135.5, 132.9,
132.1, 130.1, 130.0, 129.7 129.5, 129.3, 129.2, 18.1, 124.1, 123.9, 122.3, 63.2, 56.9,
53.6. IR (neat, cm-1): 2925, 2360, 2342, 1717, 1558, 1507, 1315, 1150, 1089, 744,
669, 517. HRMS (ESI-TLQ) m/z: [M+H]+ Calcd for C20H17NO4S 368.0948, Found:
368.0951.
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2-methoxy-3-((methylsulfonyl)methyl)isoindolin-1-one 3z. Light yellow solid (34.2
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mg, 67%). mp 121-122 ℃. H NMR (CDCl3, 600 MHz) δ 7.77 (d, J = 7.8Hz, 1H),
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1H), 3.92 (s, 3H), 3.67 (dd, J = 14.4Hz, J = 6.8Hz, 1H), 3.34 (dd, J = 13.2Hz, J =
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6.6Hz, 1H), 3.04 (s, 3H). C{H} NMR (CDCl3, 150 MHz) δ 164.1, 140.0, 132.9,
129.4, 129.2, 124.0, 123.7, 63.5, 56.6, 53.4, 42.7. IR (neat, cm-1): 2931, 2360, 2342,
1716, 1471, 1308, 1127, 996, 746, 686, 541, 504. HRMS (ESI-TLQ) m/z: [M+H]+
Calcd for C11H13NO4S 256.0634, Found: 256.0638.
3-((ethylsulfonyl)methyl)-2-methoxyisoindolin-1-one 3aa. Light yellow liquid (28.0
mg, 52%). 1H NMR (CDCl3, 600 MHz) δ 7.84 (d, J = 7.2Hz, 1H), 7.76 (d, J = 7.8Hz,
1H), 7.65-7.63 (m, 1H), 7.53 (t, J = 7.8Hz, 1H), 5.36 (dd, J = 6.6Hz, J = 4.2Hz, 1H),
3.99 (s, 3H), 3.72 (dd, J = 15.0Hz, J = 4.2Hz, 1H), 3.26 (dd, J = 15.0Hz, J = 7.2Hz,
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1H), 3.20 (dd, J = 15.0Hz, J = 7.8Hz, 2H), 1.46 (t, J = 7.8Hz, 3H). C{H} NMR
(CDCl3, 150 MHz) δ 164.2, 140.4, 132.9, 129.4, 129.2, 124.0, 123.9, 63.6, 53.5, 53.1,
49.2, 6.7. IR (neat, cm-1): 2982, 2940, 2360, 1717, 1471, 1312, 1123, 997, 796, 752,
688, 501. HRMS (ESI-TLQ) m/z: [M+H]+ Calcd for C12H15NO4S 270.0789, Found:
270.0795.
3-((cyclopropylsulfonyl)methyl)-2-methoxyisoindolin-1-one 3ab. Light yellow
liquid (31.9mg, 57%). 1H NMR (CDCl3, 600 MHz) δ 7.85 (d, J = 7.8Hz, 1H), 7.77 (d,
J = 7.8Hz, 1H), 7.63 (td, J = 7.8Hz, J = 0.6Hz 1H), 7.53 (t, J = 7.2Hz, 1H), 5.35 (dd,
J = 7.2Hz, J = 4.2Hz, 1H), 4.01 (s, 3H), 3.83 (dd, J = 14.4Hz, J = 4.2Hz, 1H), 3.37
(dd, J = 14.4Hz, J = 7.2Hz, 1H), 2.64-2.60 (m, 1H), 1.41-1.37 (m, 1H), 1.27-1.22 (m,
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1H), 1.17-1.08 (m, 2H). C{H} NMR (CDCl3, 150 MHz) δ 164.2, 140.4, 132.8,
129.3, 129.2, 123.9, 123.9, 63.6, 55.1, 53.3, 31.0, 5.30, 5.10. IR (neat, cm-1): 2921,
2850, 2360, 1716, 1653, 1558, 1471, 1318, 1291, 1123, 886, 748, 688. HRMS (ESI-
FTICR) m/z: [M+Na]+ Calcd for C13H15NNaO4S 304.0622 Found: 304.0614.
3-((butylsulfonyl)methyl)-2-methoxyisoindolin-1-one 3ac. Light yellow liquid
(22.7 mg, 38%). 1H NMR (CDCl3, 400 MHz) δ 7.85 (d, J = 7.6Hz, 1H), 7.76 (dd, J =
7.6Hz, J = 0.4Hz, 1H), 7.64 (td, J = 7.6Hz, J = 1.2Hz, 1H), 7.53 (t, J = 7.6Hz, 1H),
5.36 (dd, J = 6.8Hz, J = 4.0Hz, 1H), 3.99 (s, 3H), 3.72 (dd, J = 14.4Hz, J = 4.4Hz,
1H), 3.27 (dd, J = 14.4Hz, J = 6.8Hz, 1H), 3.19-3.14 (m, 2H), 1.92-1.83 (m, 2H),
1.56-1.46 (m, 2H), 0.98 (t, J = 7.6Hz, 3H). 13C{H} NMR (CDCl3, 100 MHz) δ 164.1,
140.4, 132.9, 129.4, 129.2, 123.9, 63.6, 54.5, 54.3, 53.0, 23.9, 21.6, 13.5. IR (neat,
cm-1): 2961, 2874, 1720, 1469, 1313, 1124, 998, 905, 749, 687, 497. HRMS (ESI-
FTICR) m/z: [M+H]+ Calcd for C14H20NO4S 298.1104 Found: 298.1108.
Product 413a was prepared according to the literature.
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3-(tosylmethyl)isoindolin-1-one 4. white solid (51.2mg, 85%). 1H NMR (CDCl3, 400
MHz) δ 7.87-7.86 (m, 3H), 7.57 (t, J = 5.2Hz, 1H), 7.50 (t, J = 7.2Hz, 1H), 7.40 (dd, J
= 12.8Hz, J = 5.2Hz, 3H), 7.09 (s, 1H), 5.08 (d, J = 7.2Hz, 1H), 3.68 (dd, J = 9.2Hz, J
= 1.2Hz, 1H), 3.13 (dd, J = 9.2Hz, J = 7.2Hz, 1H), 2.47 (s, 3H). 13C{H} NMR (CDCl3,
100 MHz) δ 169.4, 145.7, 144.0, 135.7, 132.2, 131.7, 130.3, 129.1, 128.0, 124.3,
122.3, 60.8, 50.7, 21.6.
The mechanistic study
1. (see reaction 1 in Scheme 3):
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The reaction was carried out according to the Typical procedure for the
preparation of product 3a, except TEMPO (0.4 mmol) was used. The mixture was
stirred for 17 h at 70℃. And then diluted with water and extracted with ethyl acetate
for 3 times. The combined organic layers were washed with water, saturated brine,
dried over Na2SO4, concentrated in vacuo. 1a was recovered in 70% yield. Meanwhile,
the product 4 was detected by ESI-HRMS measurement of the crude reaction mixture
(HRMS (ESI-TLQ) m/z: [M+H]+ Calcd for C19H28N2O3 333.2163, Found: 333.2173).
2. (see reaction 2 in Scheme 3):
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The reaction was carried out according to the Typical procedure for the
preparation of product 3a, except butylated hydroxytoluene (0.4 mmol) was used.
The mixture was stirred for 17 h at 70℃. And then diluted with water and extracted
with ethyl acetate for 3 times. The combined organic layers were washed with water,
saturated brine, dried over Na2SO4, concentrated in vacuo and purified by
chromatography on silica gel (elute: EtOAc/Petroleum ether 1/5 - 1/3, v/v) to give the
desired product 3a (43%, 28.5 mg). Meanwhile, 5 was obtained in 8% yield (11.7 mg)
and 6 was obtained in 18% yield (28 mg). 5: 1H NMR (CDCl3, 600 MHz) δ 7.52 (d, J
= 8.4Hz, 2H), 7.19 (d, J = 7.8Hz, 2H), 6.64 (s, 2H), 5.23 (s, 1H), 2.37 (s, 3H), 1.81 (s,
3H), 1.10 (s, 18H). 6: 1H NMR (CDCl3, 600 MHz) δ 7.44 (d, J = 8.4Hz, 2H), 7.21 (d,
J = 8.4Hz, 2H), 6.73 (s, 2H), 5.23 (s, 1H), 4.19 (s, 2H), 2.40 (s, 3H), 1.32 (s, 18H).
13C{H} NMR (CDCl3, 150 MHz) δ 154.2, 144.3, 136.0, 134.9, 129.3, 128.9, 127.6,
118.9, 63.2, 34.1, 30.0, 21.5.
3. (see reaction 3 in Scheme 3):
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The reaction was carried out according to the Typical procedure for the
preparation of product 3a, except 1,1-diphenylethylene (2.0 equiv) was used. The
mixture was stirred for 17 h at 70℃. And then diluted with water and extracted with
ethyl acetate for 3 times. The combined organic layers were washed with water,
saturated brine, dried over Na2SO4, concentrated in vacuo and purified by
chromatography on silica gel (elute: EtOAc/Petroleum ether 1/5 - 1/3, v/v) to give the
desired product 3a (51%, 33.8 mg). And when we detected the crude reaction
mixture by ESI-HRMS measurement, we could find the radical coupling product 7
(HRMS (ESI-TLQ) m/z: [M+H]+ Calcd for C21H18O2S 335.1094, Found: 335.1100.
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SUPPORTING INFORMATION. Copies of the H NMR and C NMR spectra
19
for 1c, 1f, 1j, 1k and all products. Copies of the F NMR spectra of 3g, 3s and 3w.
This material is available free of charge via the Internet at http://pubs.acs.org
ACKNOWLEDGMENT. We thank the National Natural Science Foundation
of China (No. 21702043), the Hebei Province Science Foundation for Youths
(No. B2017201041), the second batch of “Quality Experimental Projects” of Hebei
University (No. 2017-BZ-JPSY42), the "Revolution of Scientific Research Results
into Teaching Resources" of Hebei University (No. KYZJX18140) and the Hebei
Province Science Foundation for Key Program (No. B2016201031) for financial
support.
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