Ruthenium-Catalyzed Addition of Aromatic Amides to Internal Alkynes and Subsequent Intramolecular Cyclization for the Atom-Economical Synthesis of Isoindolinones

Article abstract of DOI:10.1021/acs.joc.6b02552

A selective and atom-economical synthesis of isoindolinones is described. This novel synthetic strategy involves two catalytic reactions: the ruthenium-catalyzed regioselective alkenylation of aromatic C-H bond of aromatic amides with internal alkynes, an

Full text of DOI:10.1021/acs.joc.6b02552

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Note
Ruthenium-catalyzed Addition of Aromatic Amides to
Internal Alkynes and Subsequent Intramolecular Cyclization
for the Atom-Economical Synthesis of Isoindolinones
Hiroki Miura, Sachie Terajima, Kentaro Tsutsui, and Tetsuya Shishido
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02552 • Publication Date (Web): 21 Dec 2016
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The Journal of Organic Chemistry
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Rutheniumꢀcatalyzed Addition of Aromatic Amides to Internal Alkynes and
Subsequent Intramolecular Cyclization for the AtomꢀEconomical Synthesis of
Isoindolinones
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Hiroki Miuraa,b,c*, Sachie Terajimaa, Kentaro Tsutsuia, Tetsuya Shishidoa,b,c*
a
Department of Applied Chemistry, Graduate School of Urban Environmental Sciences,
Tokyo Metropolitan University, 1ꢀ1 MinamiꢀOsawa, Hachioji, Tokyo 192ꢀ0397, Japan
b Research Center for Hydrogen Energyꢀbased Society, Tokyo Metropolitan University, 1ꢀ1
MinamiꢀOsawa, Hachioji, Tokyo 192ꢀ0397, Japan
c
Elements Strategy Initiative for Catalysts & Batteries, Kyoto University, Katsura,
Nishikyoꢀku, Kyoto 615ꢀ8520, Japan
* Corresponding author: Tel: +81ꢀ42ꢀ677ꢀ2850 Fax: +81ꢀ42ꢀ677ꢀ2821 (T. Shishido)
Eꢀmail address: miuraꢀhiroki@tmu.ac.jp (H. Miura)
Eꢀmail address: shishidoꢀtetsuya@tmu.ac.jp (T. Shishido)
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Abstract
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A selective and atomꢀeconomical synthesis of isoindolinones is described. This novel
synthetic strategy involves two catalytic reactions: the rutheniumꢀcatalyzed regioselective
alkenylation of aromatic CꢀH bond of aromatic amides with internal alkynes, and subsequent
intramolecular cyclization of the resulting alkene with amide functionalities. The addition of
only a catalytic amount of bases is required for efficient construction of the desired
isoindolinones, and no byproducts are formed in the tandem catalytic reactions. Various kinds
of aromatic amides and internal alkynes can be used in the present reactions, and the
corresponding isoindolinones bearing a quaternary carbon at the C3 position are obtained in
good to high yields.
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Keywords
Ruthenium, isoindolinones, CꢀH functionalization, aromatic amides, alkynes
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1. Introduction
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Benzoꢀfused nitrogenꢀcontaining heterocycles are ubiquitous in natural products that show
a wide range of important bioactivities, and the development of novel synthetic strategies for
their rapid and stepꢀeconomical construction is an important issue for synthetic chemists.1
Isoindolinones exhibit various important pharmaceutical and biological activities, such as
anxiolytic, antiꢀinflammatory, antiꢀfungal and antiꢀbacterial properties.2 Hence, considerable
effort has been devoted to achieve the facile synthesis of isoindolinone moieties.3 In this
regard, the transition metalꢀcatalyzed oxidative coupling of aromatic amides with alkenes is
one of the most practical methods for the preparation of isoindolinones thanks to both the
ready availability of the starting substrates and the stepꢀeconomy of the reaction (Scheme 1).
This synthetic strategy using Pd,4 Rh,5 Ru6 and Co7 catalysts involves two reactions: the
oxidative orthoꢀalkenylation of a CꢀH bond of aromatic amides with alkenes, and the
intramolecular cyclization of an amide with the resulting alkene functionality [azaꢀMichael or
azaꢀWacker reaction; Eqs. (1) and (2) in Scheme 1]. Although these tandem catalytic systems
offer many advantages, the addition of stoichiometric or catalytic amount of oxidants, such as
Cu(OAc)2 or benzoquinone, or the use of an acidic solvent is required to achieve the catalytic
alkenylation of aromatic CꢀH bonds. Thus, a novel method that can reduce the formation of
unwanted byproducts is highly desired. In the course of our studies on CꢀH bond
functionalization,8 we have demonstrated the Ruꢀcatalyzed coupling reaction of aromatic
carboxylic acids with internal alkynes to give isobenzofuranone derivatives with 100%
atomꢀefficiency.8e These reactions consist of the hydroarylation of internal alkynes and
subsequent intramolecular cyclization, in which the carboxylic functionality serves as both a
directing group for CꢀH bond activation and a nucleophilic reagent for the resulting
trisubstituted alkenes.
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Herein, we report a novel method for the synthesis of isoindolinones through the coupling
of aromatic amides with internal alkynes in the presence of Ru catalysts together with a
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catalytic amount of base [Eq. (3) in Scheme 1]. This reaction provides various isoindolinones
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Scheme 1. Isoindolinone synthesis via transition metal-catalyzed C-H alkenylation.
O
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(1)
N R
R'
Pd, Rh, Ru
oxidant
H
aza-Michael
reaction
(R' = EWG)
O
R
+
N
R'
H
Oxidative
alkenylation
O
R'
Pd, [O]
O
H
+
N R
R'
(2)
(3)
aza-Wacker
reaction
(R' = Ar, alkyl)
byproduct
R
N
H
O
O
Ru, base
R
+R'
R'
N
H
N R
R'
Hydroarylation
R'
R'
This work
R'
100% atom-efficient route!
bearing a quaternary carbon with 100% atomꢀefficiency.
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2. Results and discussion
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The reaction of Nꢀtosyl aromatic amide (1a) with an internal alkyne (2a) in the presence of
RuCl3•3H2O together with a catalytic amount of K2HPO4 in DMA at 170 oC for 48 h gave the
isoindolinone 3aa in an isolated yield of 37% (Scheme 2). The reaction proceeded selectively
to afford the isoindolinone with a methyl and benzyl groupꢀsubstituted quaternary carbon at
the C3 position. The sulfonyl substituent on the Nꢀatom of the amide plays a crucial role for
the smooth conversion of 1a, and the reaction of aromatic amides bearing H, Ph, or an
acetoxy group on the Nꢀatom resulted in no conversion of the substrates. The conversion of
Nꢀ8ꢀquinolyl aromatic amide was observed by GC analysis, and the corresponding
isoindolinone was not obtained at all. Next, we sought to identify the optimal sulfonyl
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substituent
group
for
the
present
catalytic
reactions.
Neither
(4ꢀ(trifluoromethyl)phenyl)sulfonylꢀ , (4ꢀchlorophenyl)sulfonyl , nor methylsulfonyl groups
remarkably increased the product yield. In contrast, the reaction of Nꢀbenzenesulfonyl
aromatic amide gave the corresponding isoindolinone 3ia in the highest isolated yield of 73%.
Furthermore, the yield of 3ia further increased to 80% when the reaction was allowed to
proceed for 72 h.
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Scheme 2. Effect of substituents at N-atom of aromatic amides
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O
RuCl3•3H2O
K2HPO4
O
R
Ph
N
N R
Ph
DMA
H
170 oC, 48 h
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1a–1i
(0.50 mmol)
2a
(0.75 mmol)
3
O
O
Ph
H
S
O
O
N
(Ts)
3aa
37%
3ba
0%
3ca
0%
3da
0%
3ea
0%
CF3
Cl
O
Me
O
O
O
S
S
S
S
O
O
O
O
3fa
44%
3ga
31%
3ha
3ia
73% (80%)b
48%
a Reaction conditions: 1 (0.50 mmol), 2a (0.75 mmol), RuCl3•3H2O (0.050 mmol as Ru),
K2HPO4 (0.15 mmol), DMA (1.0 mL), at 170 oC, 48 h, under Ar. b Reaction for 72 h.
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With the benzenesulfonyl group as an optimal substituent in hand, we next investigated the
effects of the catalysts and bases (Table 1). The reactions with Ru(acac)3, [RuCl2(pꢀcymene)]2
and [Cp*RuCl2]2 also gave the desired product (entries 2–4), albeit the yields of 3ia were
lower than with RuCl3•3H2O (entry 1). Although we preliminarily reported that
ZrO2ꢀsupported Ru (Ru/ZrO2) catalysts were effective for the coupling of aromatic carboxylic
acids with internal alkynes to give isobenzofuranones, the reaction with the Ru/ZrO2 catalyst
resulted in a low yield of 3ia (entry 5). Other transition metal chlorides, including
RhCl3•3H2O, PdCl2, PtCl4•nH2O, CoCl2•6H2O and CuCl2•3H2O, were totally ineffective for
the present catalytic reaction (entries 6–10). The base additives also remarkably affected the
reaction efficiency. As shown in entries 11–22 in Table 2, the highest yield of 3ia was
achieved when K2HPO4 was used as a base additive, and both stronger inorganic bases, such
as K2CO3, K3PO4 and KOtBu, and weaker bases, such as K2HPO4, KOAc and NaHCO3,
reduced the yield of the product. Although the product yield was moderate, DBU could also
be used as an organic base in the reaction. In contrast, no reaction took place in the absence of
bases or Ru catalysts (entries 23 and 24). The high temperature at around 170 oC was required
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o
to proceed the reaction efficiently, and the reaction at 150 C decreased the product yield
(entry 25). The reactions of aromatic amides with internal alkynes in the presence of Ru, Rh
or Pd catalysts together with metallic oxidants, such as Cu(OAc)2, have been reported to
selectively give sixꢀmembered isoquinolones.9 In contrast, such isoquinolones were not
formed in our Ru and base catalytic systems.
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Yield of 3ia
Entry
Catalyst
Additive
(%)b
1
RuCl3・3H2O
Ru(acac)3
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
NaH2PO4
KH2PO4
NaOAc
KOAc
73
51
36
9
2
3
[RuCl2(pꢀcymene)]2
[Cp*RuCl2]2
Ru/ZrO2
4
5
29
0
6
RhCl3・3H2O
PdCl2
7
0
8
PtCl4・nH2O
CoCl2・6H2O
CuCl2・2H2O
RuCl3・3H2O
RuCl3・3H2O
RuCl3・3H2O
RuCl3・3H2O
RuCl3・3H2O
RuCl3・3H2O
RuCl3・3H2O
RuCl3・3H2O
RuCl3・3H2O
RuCl3・3H2O
RuCl3・3H2O
RuCl3・3H2O
RuCl3・3H2O
none
0
9
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
0
14
16
23
44
43
62
47
46
0
NaHCO3
Na2HPO4
K2CO3
K3PO4
KOH
tBuONa
tBuOK
25
45
41
0
DBU
none
K2HPO4
K2HPO4
0
RuCl3・3H2O
60c
a Reaction conditions: 1i (0.50 mmol), 2a (0.75 mmol), catalyst (0.050 mmol as
metal), additive (0.15 mmol), DMA (1.0 mL), at 170 oC, 48 h, under Ar.
b Yields were determined by GLC. c Reaction at 150 oC.
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The scope of the substrates in the present Ruꢀcatalyzed reactions was investigated under the
optimized reaction conditions. The reaction of 2a with ortho methylꢀsubstituted aromatic
amides proceeded smoothly to give the corresponding isoindolinones (3ja–3ma) in good
yields. Isoindolinones with fluoro, trifluoromethyl, and phenyl substituents at the ortho
position (3na, 3oa and 3pa) were also obtained in moderate to good yields.
1HꢀBenzo[e]isoindolinone derivative 3qa could be synthesized from Nꢀsulfonyl
naphthylamide. The reactions of meta- and paraꢀsubstituted aromatic amides gave the
corresponding products (3ra–3ua) in moderate to good yields. The reactions of 1i with
unsymmetrical internal alkynes other than 2a were also examined with the present Ru
catalytic system. The reactions of 1ꢀpꢀtolylꢀ1ꢀpropyne (2b), 1ꢀphenylꢀ1ꢀbutyne (2c) and
diphenylacetylene (2d) gave the corresponding isoindolinones (3ib–3id) in moderate to good
yields. Notably, the reaction of the unsymmetrical internal alkynes proceeded regioselectively,
and other regioisomers were not obtained either immediately after the reaction or after
subsequent purification by column chromatography. In the case of the reaction of terminal
alkyne, phenylacetylene, no desired product was obtained. The sulfonyl group that plays an
important role in the catalytic reactions can be readily removed by treatment with Mg powder
in methanol to give the Nꢀprotonated isoindolinone 3ba.10 The formed NꢀH bond could also
be protected by Boc2O to provide NꢀBoc isoindolinone 4 (Scheme 3).
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Table 2. Scope of substratesa
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8
O
RuCl3•3H2O
K2HPO4
O
O
O
O
O
S
N S
R3
+
Ph
R2
R3
N
DMA, 170 oC, 48 h
Ph
H
R1
R2
R1
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1
2
3
O
O
O
O
O
O
O
O
O
N S Ph
N S Ph
N S Ph
N S Ph
O
O
Ph
O
Ph
O
Ph
Ph
b
b,c
3ia
3ja
3ka
3la
: 73% , 80%
: 46%
: 62%
: 61%
O
F
CF3
Ph
O
O
O
O
F
O
O
O
N S Ph
N S Ph
N S Ph
N S Ph
O
Ph
O
O
O
Ph
Ph
Ph
3ma
3na
3oa
3pa
: 58%
: 67%
: 30%
: 49%
O
O
O
O
O
MeO
O
O
O
N S Ph
N S Ph
N S Ph
N S Ph
O
Ph
O
Ph
O
Ph
O
Ph
3qa
3ra
3sa
3ta
: 59%
: 27%
: 71%
: 45%
O
O
O
O
O
O
O
O
N S Ph
N S Ph
N S Ph
N S Ph
O
O
O
O
Ph
: 30%
Ph
Ar
Ph
Ph
3ic
: 63%
3ua
3ib
: 47%
(Ar = p-tolyl)
3id
: 57%
a
1
2a
(0.75 mmol), RuCl3•3H2O (0.050 mmol as Ru), K2HPO4 (0.15 mmol),
Reaction conditions: (0.50 mmol),
DMA (1.0 mL), at 170 oC, 48 h, under Ar. Isolated yields. b GC yield c Yield after the reaction for 72 h.
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Figure 1 shows the time course of the reaction of 1i with 2a under the reaction conditions
described in Scheme 1. The yield of 3ia gradually increased over 48 h. On the other hand, the
rapid formation of orthoꢀalkenylated aromatic amide 5ia was observed at the initial stage of
the reaction, and the yield of 5ia gradually decreased after 6 h. These results clearly indicate
that the synthesis of isoindolinones involves two reactions: a) regioselective alkenylation of
an aromatic CꢀH bond of an amide with an internal alkyne, and b) intramolecular cyclization
of the amide with the resulting alkene functionality. The time course also suggests that the
intramolecular cyclization is much slower than the alkenylation of aromatic CꢀH bonds, and
the high temperature at around 170 oC is mainly required to proceed the cyclization step.
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80
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40
20
0
0
10
20
time / h
30
40
Figure 1. Timeꢀcourse of the reaction of 1i with 2a; yield of 3ia
(●) and 5ia (○).
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To understand the effects of Ru catalysts and bases on the present catalytic reactions, we
examined the cyclization of 5ia under several different conditions (Scheme 4). The reaction of
5ia in the presence of RuCl3•3H2O together with K2HPO4 at 170 oC for 48 h gave 3ia in 50%
yield (entry 1). On the other hand, the reaction in the absence of K2HPO4 resulted in lower
yield of 3ia (entry 2). In contrast, cyclization took place in the absence of Ru catalyst, and the
treatment of 5ia with K2HPO4 or DBU afforded 3ia in respective yields of 58% and 62%.
Furthermore, the increased yield of 3ia was obtained by the reaction with reduced amount of
K2HPO4. On the other hand, the nonꢀcatalytic treatment of 5ia in DMA resulted in a very low
yield of 3ia. These results suggest that the intramolecular cyclization of 5ia to 3ia mainly
proceeded via base catalysis.
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A plausible reaction mechanism is shown in Scheme 5. The catalytic reaction begins with
the ligand exchange of in situꢀgenerated RuII species with 1 to form ruthenium amide A. In
this step, the coordination of the oxygen atom of the sulfonyl group to the ruthenium center
may promote dissociation of the NꢀH bond of the amide group. The acidity of NꢀH bond and
basicity of sulfonyl oxygen atom may be controlled by the substituent of Nꢀatom at amide,
which concertedly functions to promote the generation of the ruthenium amide. In this regard,
benzene sulfonyl group may be the most electronicallyꢀbalanced substituent for the present
catalytic alkenylation. Subsequently, orthoꢀruthenation of A affords ruthenacycle intermediate
B accompanied by the formation of potassium dihydrogen phosphate. Regioselective insertion
of alkyne into the RuꢀC bond of B gives sevenꢀmembered ruthenacycle C.11 Successive
protonation of the RuꢀC and RuꢀN bonds of C provides orthoꢀalkenylated aromatic amide 5.
In our previous study on the Ruꢀcatalyzed coupling of aromatic acids with internal alkynes,
we proposed that the reaction included Brønsted acidꢀpromoted protonation steps based on the
results of a detailed Dꢀlabeling experiment.8,12 Finally, intramolecular cyclization of 5 by base
catalysis gives isoindolinone 3 as a final product. As described in Table 1, potassium
hydrogen phosphate was shown to be the most suitable base for the present catalytic reaction.
The conjugate base of an oxo acid, such as acetate, carbonate or phosphate, can promote the
formation of metallacycles via a concerted metalation deprotonation mechanism.13 On the
other hand, the acidic protons of potassium dihydrogen phosphate that are produced during
the dissociation of NꢀH and CꢀH bonds may efficiently promote the protonation of
intermediate C to give 5.
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Scheme 5. A plausible reaction mechanism.
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Ph
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KH2PO4
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RuX2
(X = Cl-, KHPO4 )
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3. Conclusion
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In summary, we have developed an atomꢀefficient synthesis of isoindolinones through the
Ruꢀcatalyzed addition of aromatic amides to internal alkynes and subsequent intramolecular
cyclization. The sulfonyl substituents on the Nꢀatom of amides play a crucial role in the
realization of these tandem catalytic reactions. Various isoindolinones bearing quaternary
carbons could be synthesized with 100% atomꢀefficiency. Further investigations on the
underlying mechanism and the development of novel catalytic reactions using this strategy are
underway in our laboratory.
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Experimental Section
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General Method and Materials
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All manipulations were performed under an argon atmosphere using standard Schlenk
techniques. [RuCl2(pꢀcymene)]2, all of the aromatic carboxylic acids, aromatic amides (1b
and 1c), all of the internal alkynes, inorganic bases, and DMA, were obtained commercially
and used without further purification. Aromatic amides (1d and 1e) were synthesized as
reported in the literature.14 The products of the catalytic runs were analyzed by GCꢀMS and
gas chromatography. NMR spectra were recorded on a 400 MHz (1H), 100 MHz (13C))
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1
instrument. Chemical shifts (δ) of H and 13C{1H} NMR spectra are referenced to SiMe4.
Highꢀresolution mass spectra (Fast atom bombardment (FAB)ꢀmagnetic sector analyzer) were
recorded with m-nitrobenzyl alcohol (m-NBA) as a matrix.
General Procedure for the Synthesis of N-Sulfonyl Aromatic Amides (1):
A roundꢀbottom flask under an argon atmosphere was filled with sulfonamide (1 eq), ethyl
acetate (2 M), triethylamine (2.5 eq) and DMAP (0.005 eq). A solution of acid chloride (1.1
eq) in toluene (0.8 M) was added via a syringe over 15 minutes. The mixture was stirred
under an argon atmosphere for 2 h at 55 °C, cooled to room temperature and quenched with a
solution of hydrochloric acid (0.5 mL, 3 M). The resulting mixture was then extracted with
Et2O (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered and
evaporated. The products were isolated by silicaꢀgel column chromatography
(hexane/EtOAc).
2ꢀMethylꢀNꢀtosylbenzamide (1a): white solid; yield 72 %, 2.95 g (10 mmol scale); mp
1
112ꢀ114 °C; hexane/EtOAc = 1/1; IR (Zn/SeꢀATR, neat) 1683 cm−1; H NMR (400 MHz,
CDCl3, ppm) δ 8.81 (br, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 7.6 Hz, 1H), 7.32ꢀ7.35 (m,
3H), 7.16ꢀ7.20 (m, 2H), 2.45 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 166.2,
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145.1, 137.9, 135.5, 132.0, 131.7, 131.7, 129.6, 128.5, 127.2, 125.9, 21.7, 20.1; HRMS (FAB)
m/z [M + H]+ calcd for C15H16NO3S 290.0851, found 290.0862.
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2ꢀMethylꢀNꢀ(methylsulfonyl)benzamide (1f): white solid; yield 61 %, 0.66 g (5.0 mmol
scale); mp 109ꢀ112 °C; hexane/EtOAc = 2/1; IR (Zn/SeꢀATR, neat) 1673 cm−1; 1H NMR (400
MHz, CDCl3, ppm) δ 8.68 (br, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H),
7.23ꢀ7.28 (m, 2H), 3.39 (s, 3H), 2.51 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 167.4,
138.3, 132.1, 131.9, 131.6, 127.4, 126.0, 41.6, 20.3; HRMS (FAB) m/z [M + H]+ calcd for
C9H12NO3S 214.0538, found 214.0528.
2ꢀMethylꢀNꢀ((4ꢀ(trifluoromethyl)phenyl)sulfonyl)benzamide (1g): white solid; yield 71 %,
1.27 g (4.4 mmol scale); mp 111ꢀ113 °C; hexane/EtOAc = 1/1; IR (Zn/SeꢀATR, neat) 1699
cm−1; 1H NMR (400 MHz, CDCl3, ppm) δ 8.84 (br, 1H), 8.26 (d, J = 8.4 Hz, 2H), 7.83 (d, J =
8.4 Hz, 2H), 7.36ꢀ7.43 (m, 2H), 7.18ꢀ7.22 (m, 2H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3,
ppm) δ 166.1, 141.9, 138.3, 135.6 (d, JCꢀF = 33 Hz), 132.2, 131.9, 131.4, 129.1, 127.3, 126.1
(q, JCꢀF = 3.7 Hz), 126.0, 123.0 (d, JCꢀF = 270 Hz), 20.1; HRMS (FAB) m/z [M + H]+ calcd for
C15H13F3NO3S 344.0568, found 344.0575.
Nꢀ((4ꢀChlorophenyl)sulfonyl)ꢀ2ꢀmethylbenzamide (1h): white solid; yield 82 %, 2.54 g (10
1
mmol scale); mp 124ꢀ126 °C; hexane/EtOAc = 2/1; IR (Zn/SeꢀATR, neat) 1712 cm−1; H
NMR (400 MHz, CDCl3, ppm) δ 8.89 (br, 1H), 8.06 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz,
2H), 7.34ꢀ7.42 (m, 2H), 7.17ꢀ7.21 (m, 2H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ
166.2, 140.7, 138.1, 136.8, 132.0, 131.8, 131.7, 130.0, 129.3, 127.3, 126.0, 20.1; HRMS
(FAB) m/z [M + H]+ calcd for C14H13ClNO3S 310.0305, found 310.0310.
2ꢀMethylꢀNꢀ(phenylsulfonyl)benzamide (1i): white solid; yield 87 %, 2.38 g (10 mmol scale);
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mp 90ꢀ92 °C; hexane/EtOAc = 3/1; IR (Zn/SeꢀATR, neat) 1676 cm−1; H NMR (400 MHz,
CDCl3, ppm) δ 9.01 (br, 1H), 8.10ꢀ8.12 (m, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz,
2H), 7.40 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.14ꢀ7.18 (m, 2H), 2.31 (s, 3H); 13C
NMR (100 MHz, CDCl3, ppm) δ 166.3, 138.4, 137.9, 134.0, 131.9,131.7, 131.6, 128.9, 128.4,
127.3, 125.9, 20.0; HRMS (FAB) m/z [M + H]+ calcd for C14H14NO3S 276.0694, found
276.0695.
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2,3ꢀDimethylꢀNꢀ(phenylsulfonyl)benzamide (1j): yellow solid; yield 69 %, 2.44 g (10 mmol
scale); mp 104ꢀ106 °C; hexane/EtOAc = 3/1; IR (Zn/SeꢀATR, neat) 1683 cm−1; 1H NMR (400
MHz, CDCl3, ppm) δ 8.80 (br, 1H), 8.09ꢀ8.12 (m, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.54ꢀ7.58 (m,
2H), 7.21 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 2.23 (s, 3H),
2.14 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 167.2, 144.9, 138.4, 135.4, 134.0, 133.1,
132.9, 128.9, 128.4, 125.6, 124.6, 20.2, 16.1; HRMS (FAB) m/z [M + H]+ calcd for
C15H16NO3S 290.0851, found 290.0839.
2,4ꢀDimethylꢀNꢀ(phenylsulfonyl)benzamide (1k): white solid; yield 80 %, 2.09 g (10 mmol
scale); mp 105ꢀ106 °C; hexane/EtOAc = 3/1; IR (Zn/SeꢀATR, neat) 1676 cm−1; 1H NMR (400
MHz, CDCl3, ppm) δ 8.68 (br, 1H), 8.12ꢀ8.14 (m, 2H), 7.66 (t, J = 7.4 Hz,1H), 7.54ꢀ7.58 (m,
2H), 7.33 (d, J = 8.0 Hz, 1H), 6.98ꢀ7.01 (m, 2H), 2.32 (s, 3H), 2.31 (s, 3H); 13C NMR (100
MHz, CDCl3, ppm) δ 166.0, 142.5, 138.5, 138.4, 133.9, 132.6, 129.0, 128.8, 128.4, 127.4,
126.6, 21.4, 20.2; HRMS (FAB) m/z [M + H]+ calcd for C15H16NO3S 290.0851, found
290.0865.
3ꢀMethoxyꢀ2ꢀmethylꢀNꢀ(phenylsulfonyl)benzamide (1l): white solid; yield 74 %, 2.28 g (10
mmol scale); mp 141ꢀ143 °C; hexane/EtOAc = 3/1; IR (Zn/SeꢀATR, neat) 1697 cm−1; H
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NMR (400 MHz, CDCl3, ppm) δ 8.74 (br, 1H), 8.10ꢀ8.12 (m, 2H), 7.66 (t, J = 7.6 Hz, 1H),
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7.54ꢀ7.58 (m, 2H), 7.14 (t, J = 8.0 Hz, 1H), 6.89ꢀ6.94 (m, 2H), 3.80 (s, 3H), 2.11 (s, 3H); 13C
NMR (100 MHz, CDCl3, ppm) δ 166.4, 158.1, 138.4, 134.0, 133.8, 128.9, 128.4, 126.7, 126.1,
118.7, 113.0, 55.7, 12.4; HRMS (FAB) m/z [M + H]+ calcd for C15H16NO4S 306.0800, found
306.0786.
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3ꢀFluoroꢀ2ꢀmethylꢀNꢀ(phenylsulfonyl)benzamide (1m): white solid; yield 87 %, 1.01 g (4.0
mmol scale); mp 91ꢀ93 °C; hexane/EtOAc = 1/1; IR (Zn/SeꢀATR, neat) 1708 cm−1; 1H NMR
(400 MHz, CDCl3, ppm) δ 9.06 (br, 1H), 8.10ꢀ8.12 (m, 2H), 7.68 (t, J = 7.6 Hz, 1H),
7.55ꢀ7.59 (m, 2H), 7.08ꢀ7.21 (m, 3H), 2.18 (d, J HꢀF= 2.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3, ppm) δ 165.3, 161.3 (d, JCꢀF = 245 Hz), 138.2, 134.2, 129.0, 128.4, 127.2 (d, JCꢀF = 9.0
Hz), 126.3, 125.1 (d, JCꢀF = 18 Hz), 122.8 (d, JCꢀF = 3.0 Hz), 118.5 (d, JCꢀF = 23 Hz), 11.2 (d,
JCꢀF = 6.0 Hz); HRMS (FAB) m/z [M + H]+ calcd for C14H13FNO3S 294.0600, found
294.0614.
2ꢀFluoroꢀNꢀ(phenylsulfonyl)benzamide (1n): white solid; yield 82 %, 2.29 g (10 mmol scale);
mp 125ꢀ127 °C; hexane/EtOAc = 1/1; IR (Zn/SeꢀATR, neat) 1697 cm−1; 1H NMR (400 MHz,
CDCl3, ppm) δ 9.07 (br, 1H), 8.16ꢀ8.18 (m, 2H), 7.95ꢀ8.00 (m, 1H), 7.64ꢀ7.68 (m, 1H),
7.51ꢀ7.59 (m, 3H), 7.24ꢀ7.28 (m, 1H), 7.13ꢀ7.18 (m, 1H); 13C NMR (100 MHz, CDCl3, ppm)
δ 160.3, 160.2 (d, JCꢀF = 248 Hz), 138.3, 135.6 (d, JCꢀF = 9 Hz), 134.1, 132.3, 128.9, 128.7,
126.3, 125.3 (d, JCꢀF = 3 Hz), 118.4 (d, JCꢀF = 10 Hz), 116.4 (d, JCꢀF = 24 Hz); HRMS (FAB)
m/z [M + H]+ calcd for C13H11FNO3S 280.0444, found 280.0458.
Nꢀ(Phenylsulfonyl)ꢀ2ꢀ(trifluoromethyl)benzamide (1o): white solid; yield 86 %, 2.82 g (10
1
mmol scale); mp 112ꢀ114 °C; hexane/EtOAc = 1/1; IR (Zn/SeꢀATR, neat) 1715 cm−1; H
NMR (400 MHz, CDCl3, ppm) δ 8.97 (br, 1H), 8.06ꢀ8.08 (m, 2H), 7.63ꢀ7.70 (m, 2H),
7.52ꢀ7.58 (m, 5H); 13C NMR (100 MHz, CDCl3, ppm) δ 164.5, 137.6, 134.3, 132.3, 132.1,
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270 Hz); HRMS (FAB) m/z [M + H]+ calcd for C14H11F3NO3S 330.0412, found 330.0411.
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Nꢀ(Phenylsulfonyl)ꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀcarboxamide (1p): white solid; yield 50 %, 1.69 g (10
1
mmol scale); mp 154ꢀ157 °C; hexane/EtOAc = 1/1; IR (Zn/SeꢀATR, neat) 1713 cm−1; H
NMR (400 MHz, CDCl3, ppm) δ 7.86ꢀ7.89 (m, 2H), 7.64ꢀ7.70 (m, 2H), 7.50ꢀ7.54 (m, 3H),
7.37ꢀ7.43 (m, 2H), 7.33ꢀ7.35 (m, 1H), 7.26ꢀ7.30 (m, 2H), 7.17ꢀ7.20 (m, 2H); 13C NMR (100
MHz, CDCl3, ppm) δ 166.2, 140.0, 138.7, 138.0, 133.9, 132.2, 131.8, 130.5, 129.5, ,129.1,
128.7, 128.6, 128.6, 128.4, 127.8; HRMS (FAB) m/z [M + H]+ calcd for C19H16NO3S
338.0851, found 338.0852.
Nꢀ(Phenylsulfonyl)ꢀ1ꢀnaphthamide (1q): white solid; yield 75 %, 2.33 g (10 mmol scale); mp
1
144ꢀ146 °C; hexane/EtOAc = 1/1; IR (Zn/SeꢀATR, neat) 1699 cm−1; H NMR (400 MHz,
CDCl3, ppm) δ 9.13 (br, 1H), 8.13ꢀ8.16 (m, 2H), 7.90 (d, J = 8.0 Hz, 1H), 7.78ꢀ7.80 (m, 1H),
7.63ꢀ7.67 (m, 2H), 7.52ꢀ7.56 (m, 2H), 7.45ꢀ7.49 (m, 2H), 7.34ꢀ7.38 (m, 1H); 13C NMR (100
MHz, CDCl3, ppm) δ 165.9, 138.4, 134.1, 133.6, 132.9, 129.9, 129.8, 129.0, 128.5, 128.4,
127.9, 126.8, 126.6, 124.7, 124.3; HRMS (FAB) m/z [M + H]+ calcd for C17H14NO3S
312.0694, found 312.0682.
4ꢀMethylꢀNꢀ(phenylsulfonyl)benzamide (1r): white solid; yield 75 %, 1.96 g (9.5 mmol
scale); mp 139ꢀ141 °C; hexane/EtOAc = 2/1; IR (Zn/SeꢀATR, neat) 1693 cm−1; 1H NMR (400
MHz, CDCl3, ppm) δ 9.41 (br, 1H), 8.15ꢀ8.18 (m, 2H), 7.71ꢀ7.73 (m, 2H), 7.63ꢀ7.66 (m, 1H),
7.53ꢀ7.57 (m, 2H), 7.53ꢀ7.60 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 2.36 (s, 3H); 13C NMR (100
MHz, CDCl3, ppm) δ 164.3, 144.5, 138.5, 134.0, 129.5, 129.0, 128.5, 128.2, 127.9, 21.6;
HRMS (FAB) m/z [M + H]+ calcd for C14H14NO3S 276.0694, found 276.0685.
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3ꢀMethylꢀNꢀ(phenylsulfonyl)benzamide (1s): white solid; yield 83 %, 2.17 g (9.5 mmol
scale); mp 115ꢀ117 °C; hexane/EtOAc = 2/1; IR (Zn/SeꢀATR, neat) 1668 cm−1; 1H NMR (400
MHz, CDCl3, ppm) δ 9.43 (br, 1H), 8.16ꢀ8.18 (m, 2H), 7.60ꢀ7.67 (m, 3H), 7.53ꢀ7.57 (m, 2H),
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7.35 (d, J = 7.6 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 2.33 (s, 3H); C NMR (100 MHz, CDCl3,
ppm) δ 164.5, 138.9, 138.4, 134.3, 134.0, 130.9, 129.0, 128.7, 128.5, 128.5, 124.9, 21.2;
HRMS (FAB) m/z [M + H]+ calcd for C14H14NO3S 276.0694, found 276.0681.
3ꢀMethoxyꢀNꢀ(phenylsulfonyl)benzamide (1t): yellow solid; yield 53 %, 0.94 g (5.0 mmol
scale); mp 138ꢀ140 °C; hexane/EtOAc = 2/1; IR (Zn/SeꢀATR, neat) 1683 cm−1; 1H NMR (400
MHz, CDCl3, ppm) δ 9.55 (br, 1H), 8.15ꢀ8.17 (m, 2H), 7.65 (t, J = 7.8 Hz, 1H), 7.56 (t, J =
7.8 Hz, 2H), 7.34ꢀ7.40 (m, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.06ꢀ7.08 (m, 1H), 3.77 (s, 3H); 13C
NMR (100 MHz, CDCl3, ppm) δ 164.3, 159.9, 138.3, 134.1, 132.3, 129.9, 129.0, 128.5, 120.4,
119.9, 112.3, 55.5; HRMS (FAB) m/z [M + H]+ calcd for C14H14NO4S 292.0644, found
292.0656.
Nꢀ(Phenylsulfonyl)benzamide (1u): white solid; yield 55 %, 1.28 g (9.0 mmol scale); mp
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149ꢀ152 °C; hexane/EtOAc = 1/1; IR (Zn/SeꢀATR, neat) 1695 cm−1; H NMR (400 MHz,
CDCl3, ppm) δ 9.53 (br, 1H), 8.16ꢀ8.18 (m, 2H), 7.82ꢀ7.84 (m, 2H), 7.65 (t, J = 7.4 Hz, 1H),
7.52ꢀ7.57 (m, 3H), 7.39ꢀ7.43 (m, 2H); 13C NMR (100 MHz, CDCl3, ppm) δ 164.4, 138.4,
134.1, 133.5, 131.0, 129.0, 128.9, 128.5, 127.9; HRMS (FAB) m/z [M + H]+ calcd for
C13H12NO3S 262.0538, found 262.0532.
General Procedure for the Synthesis of Isoindolinones (3):
A 20 mL Schlenk tube was charged with aromatic amide 1 (0.50 mmol), alkyne 2 (0.75
mmol), RuCl3·3H2O (0.050 mmol), dipotassium hydrogenphosphate (0.15 mmol) and DMA
(1.0 mL) under an argon atmosphere. The reaction mixture was stirred at 170 oC for 48 h on a
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hot stirrer with a cooling block. After the reaction, the reaction solution was concentrated
under reduced pressure. The products were isolated by silicaꢀgel column chromatography
(hexane/EtOAc).
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3ꢀBenzylꢀ3,7ꢀdimethylꢀ2ꢀtosylisoindolinꢀ1ꢀone (3aa): yellow solid; yield 37 %, 76.6 mg (0.50
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mmol scale); mp 135ꢀ137 °C; hexane/EtOAc = 5/1; IR (Zn/SeꢀATR, neat) 1719 cm−1; H
NMR (400 MHz, CDCl3, ppm) δ 7.95 (d, J = 8.4 Hz, 2H), 7.33 (t, J = 7.8 Hz, 1H), 7.20 (d, J
= 8.0 Hz, 2H), 6.98ꢀ7.02 (m, 4H), 6.93 (d, J = 7.6 Hz, 1H), 6.84ꢀ6.87 (m, 2H), 3.67 (d, J =
13.6 Hz, 1H), 3.41 (d, J = 13.6 Hz, 1H), 2.37 (s, 3H), 2.31 (s, 3H), 1.93 (s, 3H); 13C NMR
(100 MHz, CDCl3, ppm) δ 166.9, 150.6, 144.5, 139.0, 137.0, 134.9, 132.8, 130.5, 130.4,
129.3, 128.5, 127.7, 126.8, 125.3, 119.6, 70.9, 46.0, 26.2, 21.6, 17.6; HRMS (FAB) m/z [M +
H]+ calcd for C24H24NO3S 406.1477, found 406.1476.
3ꢀBenzylꢀ3,7ꢀdimethylꢀ2ꢀ(methylsulfonyl)isoindolinꢀ1ꢀone (3fa): yellow solid; yield 44 %,
56.9 mg (0.50 mmol scale); mp 136ꢀ138 °C; hexane/EtOAc = 5/1; IR (Zn/SeꢀATR, neat) 1715
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cm−1; H NMR (400 MHz, CDCl3, ppm) δ 7.48 (t, J = 7.6 Hz, 1H), 7.14ꢀ7.18 (m, 2H),
6.97ꢀ7.03 (m, 3H), 6.71 (d, J = 6.4 Hz, 2H), 3.63 (d, J = 14.0 Hz, 1H), 3.36 (d, J = 14.0 Hz,
1H), 3.12 (s, 3H), 2.51 (s, 3H), 1.91 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) 168.1, 151.4,
139.4, 135.3, 133.5, 130.7, 129.8, 127.9, 127.0, 125.2, 119.3, 70.9, 44.7, 42.6, 27.4, 17.6;
HRMS (FAB) m/z [M + H]+ calcd for C18H20NO3S 330.1164, found 330.1151.
3ꢀBenzylꢀ3,7ꢀdimethylꢀ2ꢀ((4ꢀ(trifluoromethyl)phenyl)sulfonyl)isoindolinꢀ1ꢀone (3ga): yellow
solid; yield 31 %, 69.8 mg (0.50 mmol scale); mp 182ꢀ185 °C; hexane/EtOAc = 5/1; IR
(Zn/SeꢀATR, neat) 1723 cm−1; 1H NMR (400 MHz, CDCl3, ppm) δ 8.27 (d, J = 8.4 Hz, 2H),
7.77 (d, J = 8.4 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.11ꢀ7.14 (m, 4H), 7.06 (d, J = 7.6 Hz, 1H),
6.91ꢀ6.92 (m, 2H), 3.75 (d, J = 13.6 Hz, 1H), 3.53 (d, J = 14.0 Hz, 1H), 2.47 (s, 3H), 2.03 (s,
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3H); 13C NMR (100 MHz, CDCl3, ppm) δ 166.9, 150.7, 143.1, 139.4, 134.9, 134.7, 133.3,
130.7, 130.4, 129.1, 127.9, 127.1, 125.7 (q, JCꢀF = 3.8 Hz), 124.9, 123.1 (q, JCꢀF = 270 Hz),
119.7, 71.3, 46.0, 26.4, 17.6; HRMS (FAB) m/z [M + H]+ calcd for C24H21F3NO3S 460.1194,
found 460.1195.
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3ꢀBenzylꢀ2ꢀ((4ꢀchlorophenyl)sulfonyl)ꢀ3,7ꢀdimethylisoindolinꢀ1ꢀone (3ha): yellow solid;
yield 48 %, 104 mg (0.50 mmol scale); mp 164ꢀ166 °C; hexane/EtOAc = 5/1; IR (Zn/SeꢀATR,
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neat) 1715 cm−1; H NMR (400 MHz, CDCl3, ppm) δ 8.07ꢀ8.09 (m, 2H), 7.43ꢀ7.48 (m, 3H),
7.10ꢀ7.12 (m, 4H), 7.04 (d, J = 7.6 Hz, 1H), 6.91ꢀ6.93 (m, 2H), 3.73 (d, J = 13.6 Hz, 1H),
3.51 (d, J = 13.6 Hz, 1H), 2.47 (s, 3H), 2.01 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ
166.9, 150.7, 140.2, 139.2, 138.3, 134.7, 133.1, 130.6, 130.4, 130.0, 129.0, 127.8, 126.9,
125.0, 119.6, 71.1, 46.0, 26.3, 17.6; HRMS (FAB) m/z [M + H]+ calcd for C23H21ClNO3S
426.0931, found 426.0928.
3ꢀBenzylꢀ3,7ꢀdimethylꢀ2ꢀ(phenylsulfonyl)isoindolinꢀ1ꢀone (3ia): yellow solid; yield 73 %,
141 mg (0.50 mmol scale); mp 142ꢀ144 °C; hexane/EtOAc = 5/1; IR (Zn/SeꢀATR, neat) 1725
cm−1; 1H NMR (400 MHz, CDCl3, ppm) δ 8.15ꢀ8.17 (m, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.51 (t,
J = 7.6 Hz, 2H), 7.43 (t, J = 7.6 Hz, 1H), 7.09ꢀ7.12 (m, 4H), 7.02 (d, J = 8.0 Hz, 1H),
6.93ꢀ6.95 (m, 2H), 3.76 (d, J = 13.6 Hz, 1H), 3.51 (d, J = 14.0 Hz, 1H), 2.47 (s, 3H), 2.02 (s,
3H); 13C NMR (100 MHz, CDCl3, ppm) δ 166.9, 150.7, 139.9, 139.2, 134.9, 133.6, 132.9,
130.5, 128.7, 128.5, 127.8, 126.9, 125.2, 119.6, 71.0, 46.1, 26.2, 17.6; HRMS (FAB) m/z [M
+ H]+ calcd for C23H22NO3S 392.1320, found 392.1301.
(E)ꢀ2ꢀmethylꢀ6ꢀ(1ꢀphenylpropꢀ1ꢀenꢀ2ꢀyl)ꢀNꢀ(phenylsulfonyl)benzamide (5ia): yellow solid;
yield 62 %, 122 mg (0.50 mmol scale); mp 63ꢀ65 °C; hexane/EtOAc = 3/1; IR (Zn/SeꢀATR,
neat) 1712 cm−1; 1H NMR (400 MHz, CDCl3, ppm) δ 7.94ꢀ7.96 (m, 2H), 7.48 (t, J = 7.4 Hz,
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1H), 7.34 (t, J = 7.4 Hz, 2H), 7.25ꢀ7.30 (m, 4H), 7.17 (d, J = 7.2 Hz, 2H), 7.09ꢀ7.12 (m, 2H),
6.41 (s, 1H), 2.28 (s, 3H), 1.89 (d, J = 1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ
166.8, 143.2, 138.0, 137.0, 136.9, 135.7, 133.9, 132.2, 130.9, 130.2, 129.3, 129.0, 128.7,
128.3, 128.2, 126.8, 126.0, 19.7, 19.3; HRMS (FAB) m/z [M + H]+ calcd for C23H22NO3S
392.1320, found 392.1328.
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3ꢀBenzylꢀ3,6,7ꢀtrimethylꢀ2ꢀ(phenylsulfonyl)isoindolinꢀ1ꢀone (3ja): yellow solid; yield 46 %,
62.7 mg (0.50 mmol scale); mp 147ꢀ150 °C; hexane/EtOAc = 5/1; IR (Zn/SeꢀATR, neat) 1717
cm−1; 1H NMR (400 MHz, CDCl3, ppm) δ 8.14ꢀ8.16 (m, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.49 (t,
J = 7.6 Hz, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.10ꢀ7.12 (m, 3H), 6.94ꢀ6.97 (m, 2H), 6.91 (d, J =
7.6 Hz, 1H), 3.71 (d, J = 13.6 Hz, 1H), 3.52 (d, J = 14.0 Hz, 1H), 2.42 (s, 3H), 2.24 (s, 3H),
1.99 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 167.2, 148.4, 139.9, 137.8, 137.6, 135.0,
134.6, 133.5, 130.5, 128.6, 128.4, 127.7, 126.8, 124.9, 119.1, 70.2, 46.0, 26.4, 19.2, 13.2;
HRMS (FAB) m/z [M + H]+ calcd for C24H24NO3S 406.1477, found 406.1459.
3ꢀBenzylꢀ3,5,7ꢀtrimethylꢀ2ꢀ(phenylsulfonyl)isoindolinꢀ1ꢀone (3ka): yellow solid; yield 62 %,
125 mg (0.50 mmol scale); mp 140ꢀ143 °C; hexane/EtOAc = 5/1; IR (Zn/SeꢀATR, neat) 1719
cm−1; 1H NMR (400 MHz, CDCl3, ppm) δ 8.14 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 8.4 Hz, 1H),
7.48 (t, J = 7.8 Hz, 2H), 7.09ꢀ7.12 (m, 3H), 6.91ꢀ6.95 (m, 3H), 6.79 (s, 1H), 3.72 (d, J = 13.6
Hz, 1H), 3.50 (d, J = 13.6 Hz, 1H), 2.42 (s, 3H), 2.36 (s, 3H), 2.00 (s, 3H); 13C NMR (100
MHz, CDCl3, ppm) δ 166.8, 151.0, 143.9, 140.0, 138.7, 135.0, 133.4, 131.5, 130.4, 128.6,
128.3, 127.7, 126.8, 122.7, 120.0, 70.8, 46.0, 26.2, 21.9, 17.4; HRMS (FAB) m/z [M + H]+
calcd for C24H24NO3S 406.1477, found 406.1489.
3ꢀBenzylꢀ6ꢀmethoxyꢀ3,7ꢀdimethylꢀ2ꢀ(phenylsulfonyl)isoindolinꢀ1ꢀone (3la): yellow solid;
yield 61 %, 127 mg (0.50 mmol scale); mp 167ꢀ169 °C; hexane/EtOAc = 5/1; IR (Zn/SeꢀATR,
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neat) 1712 cm−1; 1H NMR (400 MHz, CDCl3, ppm) δ 8.14ꢀ8.16 (m, 2H), 7.59 (t, J = 7.4 Hz,
1H), 7.50 (t, J = 7.6 Hz, 2H), 7.12ꢀ7.14 (m, 3H), 7.02 (d, J = 8.0 Hz, 1H), 6.91ꢀ6.97 (m, 3H),
3.82 (s, 3H), 3.68 (d, J = 13.6 Hz, 1H), 3.53 (d, J = 13.6 Hz, 1H), 2.36 (s, 3H), 1.99 (s, 3H);
13C NMR (100 MHz, CDCl3, ppm) δ 167.0, 157.7, 142.1, 140.0, 135.2, 133.5, 130.6, 128.7,
128.5, 127.8, 127.5, 126.8, 126.0, 120.0, 115.1, 70.3, 56.1, 46.2, 26.5, 9.7; HRMS (FAB) m/z
[M + H]+ calcd for C24H24NO4S 422.1426, found 422.1406.
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3ꢀBenzylꢀ6ꢀfluoroꢀ3,7ꢀdimethylꢀ2ꢀ(phenylsulfonyl)isoindolinꢀ1ꢀone (3ma): yellow solid;
yield 67 %, 127 mg (0.50 mmol scale); mp 189ꢀ191 °C; hexane/EtOAc = 5/1; IR (Zn/SeꢀATR,
neat) 1721 cm−1; 1H NMR (400 MHz, CDCl3, ppm) δ 8.16ꢀ8.18 (m, 2H), 7.62 (t, J = 7.6 Hz,
1H), 7.53 (t, J = 7.6 Hz, 2H), 7.20 (t, J = 8.8 Hz, 1H), 7.13ꢀ7.15 (m, 3H), 6.93ꢀ6.96 (m, 3H),
3.73 (d, J = 13.6 Hz, 1H), 3.51 (d, J = 13.6 Hz, 1H), 2.39 (d, J = 2.0 Hz, 3H), 2.01 (s, 3H);
13C NMR (100 MHz, CDCl3, ppm) δ 166.1 (d, JCꢀF = 4.2 Hz), 160.7 (d, JCꢀF = 248 Hz), 145.9,
139.7, 134.7, 133.7, 130.5, 128.6 (d, JCꢀF = 24.8 Hz), 127.9, 127.1, 126.9 (d, JCꢀF = 7.0 Hz),
125.5 (d, JCꢀF = 19.3 Hz), 120.6 (d, JCꢀF = 8.5 Hz), 120.2 (d, JCꢀF = 25 Hz), 70.6, 46.0, 26.2,
8.9 (d, JCꢀF = 3.8 Hz); HRMS (FAB) m/z [M + H]+ calcd for C23H21FNO3S 410.1226, found
410.1208.
3ꢀBenzylꢀ7ꢀfluoroꢀ3ꢀmethylꢀ2ꢀ(phenylsulfonyl)isoindolinꢀ1ꢀone (3na): yellow solid; yield
30 %, 59.3 mg (0.50 mmol scale); mp 216ꢀ218 °C; hexane/EtOAc = 5/1; IR (Zn/SeꢀATR,
neat) 1736 cm−1; 1H NMR (400 MHz, CDCl3, ppm) δ 8.16ꢀ8.19 (m, 2H), 7.61 (t, J = 7.4 Hz,
1H), 7.50ꢀ7.58 (m, 3H), 7.13ꢀ7.14 (m, 3H), 6.95ꢀ7.03 (m, 4H), 3.81 (d, J = 13.6 Hz, 1H), 3.50
(d, J = 14 Hz, 1H), 2.05 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 161.7 (d, JCꢀF = 253 Hz),
157.8, 152.4, 139.4, 135.5 (d, JCꢀF = 7.6 Hz), 134.4, 133.9, 130.4, 128.8, 128.6, 128.0, 127.2,
118.2 (d, JCꢀF = 4.1 Hz), 115.8, 115.6, 71.8, 45.9, 26.1; HRMS (FAB) m/z [M + H]+ calcd for
C22H19FNO3S 396.1070, found 396.1076.
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3ꢀBenzylꢀ3ꢀmethylꢀ2ꢀ(phenylsulfonyl)ꢀ7ꢀ(trifluoromethyl)isoindolinꢀ1ꢀone (3oa): yellow
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solid; yield 49 %, 108 mg (0.50 mmol scale); mp 191ꢀ193 °C; hexane/EtOAc = 3/1; IR
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(Zn/SeꢀATR, neat) 1736 cm−1; H NMR (400 MHz, CDCl3, ppm) δ 8.19ꢀ8.21 (m, 2H),
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7.60ꢀ7.66 (m, 3H), 7.53 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 4.4 Hz, 1H), 7.12ꢀ7.13 (m, 3H),
6.91ꢀ6.93 (m, 2H), 3.76 (d, J = 13.6 Hz, 1H), 3.58 (d, J = 14.0 Hz, 1H), 2.09 (s, 3H); 13C
NMR (100 MHz, CDCl3, ppm) δ 162.7, 152.2, 139.3, 134.3, 133.9, 133.0, 130.4, 128.9, 128.7,
128.0, 127.7 (q, JCꢀF = 35 Hz), 127.2, 126.4 (q, JCꢀF = 5.7 Hz), 126.2, 125.3, 122.0 (q, JCꢀF
=
272 Hz), 71.0, 46.0, 25.6; HRMS (FAB) m/z [M + H]+ calcd for C23H19F3NO3S 446.1038,
found 446.1030.
3ꢀBenzylꢀ3ꢀmethylꢀ7ꢀphenylꢀ2ꢀ(phenylsulfonyl)isoindolinꢀ1ꢀone (3pa): yellow solid; yield
58 %, 85.6 mg (0.50 mmol scale); mp 192ꢀ194 °C; hexane/EtOAc = 3/1; IR (Zn/SeꢀATR,
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neat) 1723 cm−1; H NMR (400 MHz, CDCl3, ppm) δ 8.09ꢀ8.11 (m, 2H), 7.60 (t, J = 7.6 Hz,
1H), 7.52 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.24ꢀ7.33 (m, 5H), 7.12ꢀ7.17 (m, 5H),
6.95ꢀ6.97 (m, 2H), 3.95 (d, J = 13.6 Hz, 1H), 3.41 (d, J = 13.6 Hz, 1H), 2.08 (s, 3H); 13C
NMR (100 MHz, CDCl3, ppm) δ 165.3, 151.3, 141.9, 140.0, 136.6, 134.7, 133.5, 133.0, 130.8,
130.5, 129.3, 128.7, 128.3, 128.0, 127.8, 127.8, 126.9, 124.2, 120.8, 70.4, 46.6, 25.6; HRMS
(FAB) m/z [M + H]+ calcd for C28H24NO3S 454.1477, found 454.1496.
3ꢀBenzylꢀ3ꢀmethylꢀ2ꢀ(phenylsulfonyl)ꢀ2,3ꢀdihydroꢀ1Hꢀbenzo[e]isoindolꢀ1ꢀone (3qa): yellow
solid; yield 59 %, 128 mg (0.50 mmol scale); mp 192ꢀ195 °C; hexane/EtOAc = 5/1; IR
(Zn/SeꢀATR, neat) 1706 cm−1; 1H NMR (400 MHz, CDCl3, ppm) δ 8.87 (d, J = 8.4 Hz, 1H),
8.20ꢀ8.22 (m, 2H), 8.04 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.50ꢀ7.59 (m, 5H), 7.29
(d, J = 8.0 Hz, 1H), 7.05ꢀ7.06 (m, 3H), 6.95ꢀ6.98 (m, 2H), 3.87 (d, J = 14.0 Hz, 1H), 3.62 (d,
J = 14.0 Hz, 1H), 2.08 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 170.0, 151.3, 139.9,
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134.8, 134.7, 133.6, 132.9, 130.4, 128.8, 128.7, 128.5, 128.3, 127.9, 127.1, 127.0, 123.7,
121.8, 119.0, 71.2, 45.5, 25.8; HRMS (FAB) m/z [M + H]+ calcd for C26H22NO3S 428.1320,
found 428.1326.
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3ꢀBenzylꢀ3,5ꢀdimethylꢀ2ꢀ(phenylsulfonyl)isoindolinꢀ1ꢀone (3ra): yellow solid; yield 27 %,
52.2 mg (0.50 mmol scale); mp 208ꢀ210 °C; hexane/EtOAc = 5/1; IR (Zn/SeꢀATR, neat) 1717
cm−1; 1H NMR (400 MHz, CDCl3, ppm) δ 8.15ꢀ8.17 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.50 (t,
J = 7.6 Hz, 2H), 7.38ꢀ7.39 (m, 2H), 7.08ꢀ7.13 (m, 4H), 6.94ꢀ6.96 (m, 2H), 3.75 (d, J = 13.6
Hz, 1H), 3.52 (d, J = 14.0 Hz, 1H), 2.35 (s, 3H), 2.01 (s, 3H); 13C NMR (100 MHz, CDCl3,
ppm) δ 166.4, 147.3, 139.8, 138.9, 134.8, 134.7, 133.6, 130.5, 128.7, 128.4, 128.1, 127.8,
126.9, 124.5, 122.0, 72.1, 45.9, 26.1, 21.2; HRMS (FAB) m/z [M + H]+ calcd for C23H22NO3S
392.1320, found 392.1328.
3ꢀBenzylꢀ3,6ꢀdimethylꢀ2ꢀ(phenylsulfonyl)isoindolinꢀ1ꢀone (3sa): yellow solid; yield 71 %,
136 mg (0.50 mmol scale); mp 204ꢀ206 °C; hexane/EtOAc = 5/1; IR (Zn/SeꢀATR, neat) 1724
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cm−1; H NMR (400 MHz, CDCl3, ppm) δ 8.14ꢀ8.16 (m, 2H), 7.58 (t, J = 7.4 Hz, 1H),
7.46ꢀ7.51 (m, 3H), 7,17 (d, J = 8.4 Hz, 1H), 7.10ꢀ7.12 (m, 3H), 6.98 (s, 1H), 6.92ꢀ6.94 (m,
2H), 3.75 (d, J = 14.0 Hz, 1H), 3.52 (d, J = 13.6 Hz, 1H), 2.43 (s, 3H), 2.02 (s, 3H); 13C NMR
(100 MHz, CDCl3, ppm) δ 166.2, 150.3, 144.7, 139.9, 134.8, 133.6, 130.5, 129.8, 128.7,
128.4, 127.8, 126.9, 125.5, 124.4, 122.6, 72.0, 46.0, 26.0, 22.2; HRMS (FAB) m/z [M + H]+
calcd for C23H22NO3S 392.1320, found 392.1328.
3ꢀBenzylꢀ6ꢀmethoxyꢀ3ꢀmethylꢀ2ꢀ(phenylsulfonyl)isoindolinꢀ1ꢀone (3ta): yellow solid; yield
45 %, 94.9 mg (0.50 mmol scale); mp 165ꢀ168 °C; hexane/EtOAc = 5/1; IR (Zn/SeꢀATR,
neat) 1713 cm−1; 1H NMR (400 MHz, CDCl3, ppm) δ 8.16ꢀ8.18 (m, 2H), 7.59 (t, J = 7.4 Hz,
1H), 7.50 (t, J = 7.8 Hz, 2H), 7.12ꢀ7.15 (m, 4H), 7.08 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 2.4 Hz,
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1H), 6.94ꢀ6.97 (m, 2H), 3.75 (s, 3H), 3.73 (d, J = 13.6 Hz, 1H), 3.51 (d, J = 13.6 Hz, 1H),
2.00 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 166.3, 160.1, 142.4, 139.8, 134.8, 133.7,
130.5, 129.2, 128.7, 128.4, 127.8, 126.9, 123.2, 122.5, 106.2, 72.0, 55.6, 46.0, 26.0; HRMS
(FAB) m/z [M + H]+ calcd for C23H22NO4S 408.1270, found 408.1277.
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3ꢀBenzylꢀ3ꢀmethylꢀ2ꢀ(phenylsulfonyl)isoindolinꢀ1ꢀone (3ua): yellow solid; yield 57 %, 106
mg (0.50 mmol scale); mp 158ꢀ161 °C; hexane/EtOAc = 5/1; IR (Zn/SeꢀATR, neat) 1731
cm−1; 1H NMR (400 MHz, CDCl3, ppm) δ 8.16ꢀ8.19 (m, 2H), 7.57ꢀ7.60 (m, 3H), 7.51 (t, J =
7.8 Hz, 2H), 7.36 (t, J = 7.8 Hz, 1H), 7.24 (t, J = 6.0 Hz, 1H), 7.09ꢀ7.11 (m, 3H), 6.93ꢀ6.95
(m, 2H), 3.79 (d, J = 13.6 Hz, 1H), 3.52 (d, J = 13.6 Hz, 1H), 2.05 (s, 3H); 13C NMR (100
MHz, CDCl3, ppm) δ 166.2, 149.9, 139.8, 134.7, 1337, 133.6, 130.5, 128.7, 128.4, 128.0,
127.8, 126.9, 124.5, 122.2, 72.2, 45.9, 25.9; HRMS (FAB) m/z [M + H]+ calcd for
C22H20NO3S 378.1164, found 378.1174.
3,7ꢀDimethylꢀ3ꢀ(4ꢀmethylbenzyl)ꢀ2ꢀ(phenylsulfonyl)isoindolinꢀ1ꢀone (3ib): yellow solid;
yield 47 %, 94.7 mg (0.50 mmol scale); mp 121ꢀ123 °C; hexane/EtOAc = 5/1; IR (Zn/SeꢀATR,
neat) 1725 cm−1; 1H NMR (400 MHz, CDCl3, ppm) δ 8.08ꢀ8.10 (m, 2H), 7.52 (t, J = 7.6 Hz,
1H), 7.43 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.96 (d, J =
7.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 2H), 6.74 (d, J = 8.0 Hz, 2H), 3.62 (d, J = 13.6 Hz, 1H), 3.41
(d, J = 13.6 Hz, 1H), 2.40 (s, 3H), 2.16 (s, 3H), 1.93 (s, 3H); 13C NMR (100 MHz, CDCl3,
ppm) δ 166.9, 150.8, 140.0, 139.1, 136.4, 133.5, 132.9, 131.7, 130.5, 130.4, 128.7, 128.5,
128.5, 125.3, 120.0, 71.2, 45.7, 26.2, 21.0, 17.6; HRMS (FAB) m/z [M + H]+ calcd for
C24H24NO3S 406.1477, found 406.1489.
3ꢀBenzylꢀ3ꢀethylꢀ7ꢀmethylꢀ2ꢀ(phenylsulfonyl)isoindolinꢀ1ꢀone (3ic): yellow solid; yield 63 %,
128 mg (0.50 mmol scale); mp 153ꢀ156 °C; hexane/EtOAc = 5/1; IR (Zn/SeꢀATR, neat) 1720
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cm−1; 1H NMR (400 MHz, CDCl3, ppm) δ 8.17ꢀ8.19 (m, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.51 (t,
J = 7.6 Hz, 2H), 7.40 (t, J = 7.6 Hz, 1H), 7.09ꢀ7.15 (m, 4H), 6.91ꢀ6.94 (m, 2H), 6.84 (d, J =
7.6 Hz, 1H), 3.61ꢀ3.69 (m, 2H), 2.91ꢀ2.99 (m, 1H), 2.53 (s, 3H), 2.09ꢀ2.18 (m, 1H), 0.36 (t, J
= 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 167.6, 148.7, 139.7, 139.1, 135.0, 133.6,
132.9, 130.7, 130.5, 128.7, 128.6, 127.8, 126.9, 126.2, 119.7, 75.7, 45.7, 30.6, 17.7, 8.1;
HRMS (FAB) m/z [M + H]+ calcd for C24H24NO3S 406.1477, found 406.1476.
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3ꢀBenzylꢀ7ꢀmethylꢀ3ꢀphenylꢀ2ꢀ(phenylsulfonyl)isoindolinꢀ1ꢀone (3id): yellow solid; yield
30 %, 68.4 mg (0.50 mmol scale); mp 221ꢀ223 °C; hexane/EtOAc = 5/1; IR (Zn/SeꢀATR,
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neat) 1713 cm−1; H NMR (400 MHz, CDCl3, ppm) δ 7.38ꢀ7.45 (m, 2H), 7.31ꢀ7.33 (m, 3H),
7.20ꢀ7.25 (m, 5H), 7.12ꢀ7.14 (m, 1H), 7.05ꢀ7.09 (m, 4H), 7.00ꢀ7.03 (m, 2H), 6.96ꢀ6.98 (m,
1H), 4.78 (d, J = 13.2 Hz, 1H), 3.66 (d, J = 13.2 Hz, 1H), 2.46 (s, 3H); 13C NMR (100 MHz,
CDCl3, ppm) δ 167.3, 151.2, 139.2, 138.7, 134.0, 133.4, 133.2, 130.7, 130.4, 129.1, 128.7,
128.5, 128.4, 128.2, 128.1, 127.7, 126.8, 125.9, 120.6, 74.0, 52.1, 42.1, 17.5; HRMS (FAB)
m/z [M + H]+ calcd for C28H24NO3S 454.1477, found 454.1499.
Desulfonylation of 3ia
A 20 mL Schlenk tube was charged with 3ia (0.30 mmol), Mg (3.0 mmol) and MeOH (2.0
o
mL) under an argon atmosphere. The reaction mixture was stirred at 80 C for 24 h on a hot
stirrer with a cooling block. After the reaction mixture was allowed to cool, the reaction
solvent was removed under reduced pressure. The product 3ba was isolated by silicaꢀgel
column chromatography (hexane/EtOAc = 3/1).
3ꢀBenzylꢀ3,7ꢀdimethylisoindolinꢀ1ꢀone (3ba): yellow solid; yield 64 %, 48.8 mg (0.30 mmol
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scale); mp 53ꢀ55 °C; IR (Zn/SeꢀATR, neat) 1681 cm−1; H NMR (400 MHz, CDCl3, ppm) δ
7.34 (t, J = 7.6 Hz, 1H), 7.12ꢀ7.18 (m, 4H), 7.08 (d, J = 7.6 Hz, 1H), 7.03ꢀ7.05 (m, 2H), 6.38
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