TiCl 4 -Mediated Synthesis of 3,4-Hetero-Disubstituted Isocoumarins by Means of Isocyanide Insertion Reactions

Article abstract of DOI:10.1055/s-0036-1591733

The isocyanide insertion into sulfanyl-phthalides under Lewis acid conditions is reported with full details. This sequential three-component reaction affords a new straightforward and highly convenient method for the preparation of 3-amino-4-sulfanyl isocoumarins, the potential of which is still unexplored.

Full text of DOI:10.1055/s-0036-1591733

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–L
paper
A
en
S. Ponra et al.
Paper
Synthesis
TiCl4-Mediated Synthesis of 3,4-Hetero-Disubstituted Isocoumarins
by Means of Isocyanide Insertion Reactions
Sudipta Ponraa,c
Aude Nyadanub,c
Sylvie Maurinc
Laurent El Kaïm*b
Laurence Grimaud*c
Maxime R. Vitale*a
O
COOH
TiCl4
O
R1
R1
two steps or
one-pot two steps
CHO
NHR3
0
0
0
0
0-
0
0
1
5-
7
2
9
8-
0
1
0
+
SR2
0
0
0
0
0-
0
0
3
3-
9
0
4
1-
8
2
2
R2SH
R3NC
35 examples
14-94% yield
3,4-hetero-disubstituted
isocoumarins
a Chimie ParisTech, PSL Research University, CNRS, Institut de Recherche
de Chimie Paris (IRCP), 75005 Paris, France
maxime.vitale@chimie-paristech.fr
b LSO (UMR 7652), École Polytechnique - ENSTA ParisTech, Université
Paris-Saclay, 91120, Palaiseau, France
laurent.elkaim@ensta-paristech.fr
c PASTEUR, Département de Chimie, École Normale Supérieure, PSL
Research University, Sorbonne Universités, UPMC Univ. Paris 06, CNRS,
75005 Paris, France
laurence.grimaud@ens.fr
Received: 11.10.2017
Accepted after revision: 07.11.2017
Published online: 13.12.2017
OH
O
O
OH
O
R1
O
O
O
DOI: 10.1055/s-0036-1591733; Art ID: ss-2017-t0657-op
R
Me
X
O
MeO
Me
Cl
Me
MeO2C
O
Abstract The isocyanide insertion into sulfanyl-phthalides under Lewis
acid conditions is reported with full details. This sequential three-com-
ponent reaction affords a new straightforward and highly convenient
method for the preparation of 3-amino-4-sulfanyl isocoumarins, the
potential of which is still unexplored.
X = Cl, OR
oopsolactone (R = H)
antifungal
cephalosol
4-Cl-isocoumarins
protease inhibitors
polygolide (R = OMe)
antimicrobial
anti-inflammatory
O
Key words isocyanides, isocoumarins, thio-Passerini reaction, thiocar-
bonyl surrogates
O
O
R1
3-amino-4-aryl isocoumarins
OR3
anticholesteremic
and anti-arteriosclerotic
N
H
Isocoumarins constitute a family of synthetic or natu-
rally occurring molecules that demonstrate an exceptional-
ly wide array of biological activities and, for more than half
a century, have been the cornerstone of many organic and
pharmaceutical chemistry research programs.1,2 Among
this class, several 3,4-disubstituted isocoumarins including
oospolactone, polygolide and cephalosol have exhibited in-
teresting antifungal, anti-inflammatory and antimicrobial
activities.3 Furthermore, some 4-chloro-substituted ana-
logues are very potent protease inhibitors with potential
applications in Alzheimer’s disease, while various 3-amino-
4-aryl derivatives have demonstrated encouraging anti-
cholesteremic and anti-arteriosclerotic activities (Figure 1).4
As a consequence, the development of new synthetic
routes to 3,4-disubstituted isocoumarin scaffolds has be-
come a very active field of research.2–7 Whereas the vast
majority of the reported methods rely on the use of internal
alkynes by means of transition-metal-catalyzed or electro-
philic annulation reactions,1d,5,6 the regioselective incorpo-
ration of heteroatoms on position 3 and/or 4 still remains a
significant challenge.
R2
Figure 1 Representative biologically active 3,4-disubstituted isocou-
marins
In this area, isocyanide-based insertion reactions have
emerged as particularly promising strategies.8,9 In 2010,
Marcaccini et al. reported that, starting from 2-formylben-
zoic acid, an isonitrile and an amine, various 3,4-diamino-
isocoumarins could be obtained (Scheme 1, eq. 1).8a Later,
by replacing the amine partner with malononitrile, Solei-
mani et al. were able to extend this work to the synthesis of
3,4-pyrazolo-isocoumarins (Scheme 1, eq. 2).8b
In continuation of our interest in isocyanide chemis-
try,10 we recently reported the preparation of various
thiophthalides by a formal thio-Passerini reaction.11 During
this work, we incidentally discovered that, in specific cases,
valuable 3-amino-4-sulfanyl isocoumarins could be ob-
tained (Scheme 1, eq. 3). We report herein with full details
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–L

B
S. Ponra et al.
Paper
Synthesis
this regioselective method for access to 3,4-hetero-disub-
stituted isocoumarins, starting from sulfanyl-phthalides or
directly from 2-formylbenzoic acids.
For this purpose, in dichloromethane at room tempera-
ture, 3-phenylsulfanyl-phthalide (1a) was initially submit-
ted to a variety of isocyanides 2b–h (1.2 equiv) and TiCl4
(1.0 equiv) (Scheme 3). To our delight, the desired isocya-
nide insertion reaction took place regardless of the aliphatic
or aromatic nature of the isocyanide engaged in the process.
Accordingly, secondary alkyl as well as primary alkyl isocy-
anides 2b–e afforded the desired 3,4-disubstituted isocou-
marins 3ab–ae with up to 94% yield, while aromatic isocya-
nides 2f and 2g afforded 3af and 3ag in 86% and 79% yield,
respectively. As a probable consequence of competitive po-
lymerization processes, the use of electron-rich 2-me-
thoxyphenyl isocyanide 2h only afforded a 14% yield of 3ah.
Marcaccini et al. (eq. 1)
O
O
R2NH2
O
OH
O
R1NC
RNC
+
MeOH, rt
NHR1
NHR2
Soleimani et al. (eq. 2)
O
O
NC
CN
O
OH
O
+
cat. Et3N
NR
CH2Cl2, rt
NC
NH2
O
O
This work (eq. 3)
O
TiCl4 (1 equiv)
CH2Cl2, rt, 1 h
O
+
RNC
O
O
R
(1.2 equiv)
N
O
H
TiCl4
SPh
R1
3ab–ah
1a
R3NC
R1
2b–h
+
SPh
O
SR2
Scheme 1 State of the art and the aim of this work
NHR3
CH2Cl2, rt
2b: R = Cy, 2c: R = nPent, 2d: R = Bn, 2e: R = CH2CO2Me
2f: R = 2,6-(Me)2C6H3, 2g: R = 4-ClC6H4; 2h: R = 2-(MeO)C6H4
SR2
O
O
O
O
O
O
We previously reported that, upon reaction with isoni-
triles and TiCl4 at room temperature, 3-(tert-butylsulfanyl)-
phthalides allowed the formation of a variety of thiophtha-
lides in respectable yields (Scheme 2, eq. 1).11 During the
related optimization studies, we alternatively witnessed an
interesting reactivity dichotomy when 3-phenylsulfanyl-
phthalide (1a) was employed. Indeed, with tert-butyl isocy-
anide (2a), this particular substrate in which solely the S-
substitution changes led cleanly to the 3-amino-4-sulfanyl
isocoumarin 3aa in a good 76% yield (Scheme 2, eq. 2).
While, to the best of our knowledge, the preparation of such
heterocyclic scaffolds has been scarcely studied,7g,h the po-
tential of an original synthetic access to these 3,4-hetero-
disubstituted isocoumarins encouraged us to study the
scope and limitations of this novel transformation.
Bn
nPent
Cy
N
N
H
N
H
H
SPh
SPh
SPh
3ad
68%
3ac
87%
3ab
94%
O
O
O
Y
O
CO2Me
N
N
H
H
3ae
70%
SPh
SPh
3af Y = 2,6-Me2, 86%
3ag Y = 4-Cl, 79%
3ah Y = 2-MeO, 14%
Scheme 3 Scope of various isocyanides in the TiCl4-promoted isocya-
nide insertion reaction into sulfanyl-phthalide 1a
We next studied the impact of the sulfur atom substitu-
tion on the overall efficiency of the isocyanide insertion
process. A large panel of diversely functionalized sulfanyl-
phthalides was prepared according to a straightforward
protocol in which 2-formylbenzoic acids 4a–c and various
thiols 5a–r were refluxed in toluene in the presence of Mg-
SO4 (Scheme 4). Pleasingly, this method proved to be quite
robust and allowed the required sulfanyl-phthalides 1b–r,
1a′ and 1l′′ to be obtained in good to excellent yields (42–
98%), apart from in the case of 1-naphthyl-substituted com-
pound 1k (18% yield).
Submitting S-aryl substituted sulfanyl-phthalides to the
isocyanide-insertion conditions afforded the desired iso-
coumarin derivatives in good to excellent yields (Scheme 5).
The substitution on the aromatic core poorly influences the
efficiency of the reaction as electron-donating groups such
as methoxy or alkyl give yields similar to those obtained
(eq. 1)
R1
O
O
R2NC (1.2 equiv)
TiCl4 (2.0 equiv)
R1
S
O
CH2Cl2, rt
StBu
44–80% yield
O
R2HN
thiophthalides
O
(eq. 2)
tBuNC 2a (1.2 equiv)
O
O
TiCl4 (1.0 equiv)
O
NHtBu
CH2Cl2, rt
76% yield
SPh
SPh
1a
3aa
3,4-disubstituted
isocoumarin
Scheme 2 Divergent synthesis of thiophthalides and 3,4-disubstituted
isocoumarin 3aa
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–L

C
S. Ponra et al.
Paper
Synthesis
O
O
S
R1
COOH
O
R1
R1
R1
PTSA (5 mol%)
R2SH
TiCl4 (1 equiv)
O
O
+
CyNC
O
+
MgSO4
toluene, reflux
CHO
Cy
CH2Cl2, 25 °C, 1 h
(1.2 equiv)
N
H
SR2
4a–c
5a–r
1b–r,
1a', 1l''
S
1b–l,
1a', 1l''
2b
3bb–3lb
3a'b, 3l''b
Ar
Ar
O
4a: R1 = H
4b: R1 = Me
4c: R1 = MeO
O
O
O
O
O
O
S
O
O
O
O
Cy
Cy
Cy
N
N
N
H
O
O
O
H
H
S
S
Y
Y
S
S
S
S
Br
Y
Y
X
Br
3bb, X = 4-Me, 69%
3cb, X = 4-MeO, 65%
3db, X = 4-tBu, 76%
3eb, X = 4-F, 68%
3fb, 4-Br, 84%
3gb, 3-Br, 92%
3hb, 2-Br, 82%
3ib, Y = Me, 89%
3jb, Y = MeO, 55%
X
1f, 4-Br, 98% 1i, Y = Me, 87% 1k, 1-naphthyl, 18%
1g, 3-Br, 96% 1j, Y = MeO, 97% 1l, 2-naphthyl, 71%
1h, 2-Br, 42%
1b, X = Me, 98%
1c, X = 4-MeO, 76%
1d, X = 4-tBu, 95%
1e, X = 4-F, 57%
O
O
O
O
O
O
MeO
O
O
Me
Me
MeO
O
Cy
Cy
N
N
O
O
Cy
O
H
S
H
N
S
H
S
S
S
S
R
Ph
Ph
1a', 84%
2-Naphthyl
1m, R = nDodecyl, 94%
1n, R = nHex, 93%
1o, R = Cy, 92%
1p, R = tBu, 76%
1q, R = Bn, 98%
1l'', 96%
3a'b, 93%
3kb, 1-naphthyl, 68%
3lb, 2-naphthyl, 84%
3l''b, 86%
Scheme 5 Evaluation of the scope of the reaction starting from vari-
ous S-aryl-substituted sulfanyl-phthalides and cyclohexylisocyanide
(CyNC)
1r, R = CH2CO2Me, 78%
Scheme 4 Preparation of a wide variety of sulfanyl-phthalides 1
Table 1 Evaluation of S-Alkyl-Substituted Sulfanyl-phthalides
with electron-withdrawing groups such as halogen atoms.
The ortho, meta or para position of the substituent seemed
to have no effect on the reaction as isocoumarins 3fb–hb
were obtained in almost identical yields.
O
O
O
O
S
O
(1 equiv)
TiCl4
R2NC
R2
N
CH2Cl2
25 °C, 1 h
H
2
S
O
S
The scope was next examined for S-alkyl-substituted
phthalides. Depending on the nature of the starting thiol,
different results were observed. Primary thiols with long al-
iphatic chains gave the expected isocoumarins in good
yields (Table 1, entries 1–3). However, secondary or benzyl-
ic thiols afforded the desired products along with substan-
tial amounts (16–32%) of the corresponding thiophthalides
6 (Table 1, entries 5–7). We surmised that such outcomes
could be rationalized by the ability of the S-substituent to
stabilize the formed carbocation to allow the final 1,5-acyl
transfer (Scheme 6). This hypothesis was further confirmed
by the formation of 6b as the major product in 70% isolated
yield when using tert-butyl thiol (Table 1, entry 8).
These experimental results led us to propose a plausible
mechanistic path for the isocoumarin synthesis (Scheme 6).
The complexation of the Lewis acid with the starting sulfa-
nyl-phthalide 1 induces the formation of the thiocarbenium
intermediate A, which is electrophilic enough to promote
nucleophilic addition of the isocyanide. The resulting nitril-
ium species B is then trapped intramolecularly to give C. Af-
ter tautomerization, the latter evolves toward the pyrylium
R2HN
R1
R1
(1.2 equiv)
3ma, mb,
3nb–rb
6b, d
1m–r
Entry Phthalide 1
Isocyanide 2
(R2)
Isocoumarin 3 Thiophthalide 6
(R1)
(yield)a
(yield)a
b
1
2
3
4
5
6
7
8
1m (nDodecyl)
2b (Cy)
3mb (93%)
3ma (50%)c
3nb (93%)
3rb (24%)
3ob (68%)
3od (55%)
3qb (70%)
3pb (16%)
–
1m (nDodecyl)
1n (nHex)
1r (CH2CO2Me)
1o (Cy)
2a (tBu)
2b (Cy)
2b (Cy)
2b (Cy)
2d (Bn)
2b (Cy)
2b (Cy)
–
b
b
–
b
–
6b (32%)
6d (29%)
6b (16%)
6b (70%)
1o (Cy)
1q (Bn)
1p (tBu)
a Yield of isolated product.
b Not detected by 1H NMR spectroscopy of the crude reaction mixture.
c Partial deprotection of isocoumarin 3ma was additionally observed (3ma′,
R2 = H, 12%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–L

D
S. Ponra et al.
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Synthesis
D, which is most probably responsible for the intense dark-
blue color of the reaction mixture. Indeed, when adding
water at the end of the reaction, the color vanishes and the
expected isocoumarin 3 is formed. This hypothesis is rather
consistent with the need for a stoichiometric amount of
Lewis acid as the pyrylium species D is still linked to one
molecule of TiCl4. In the case of more labile R1 substituents,
intermediate C could evolve through the loss of this group
and competitive 1,5-acyl transfer from O to S, which would
give the corresponding thiophthalide 6.
O
1) TiCl4 (0.2 equiv) then
O
R1
R1
2) R3NC (2, 1.5 equiv)
TiCl4 (1.0 equiv)
O
OH
O
2
+
R SH
NHR3
CH2Cl2, rt
MS 4 Å
SR2
4a–c
5
3
(1.1 equiv)
O
O
O
O
NH
R3
NH
R3
S
S
pTol
nDodecyl
3ma, R3 = tBu, 48%
3mb, R3 = Cy, 73%
3bb, R3 = Cy, 56%
3bc, R3
=
nPent, 73%
Cl4Ti
Cl4Ti
3mc, R3
=
nPent, 38%
3bf, R3 = 2,6-Me2C6H3, 49%
Cl4Ti
O
S
O
O
S
3md, R3 = Bn, 61%
3mf, R3 = 2,6-Me2C6H3, 51%
R2NC
O
O
O
O
O
O
S
R2
R2
N
R1
N
O
S
R1
A
C
B
R1
R1
NH
Cy
NH
Cy
S
R2
pTol
3ab, R2 = Ph, 33%
TiCl4
3b'b, R' = Me, 52%
3b"b, R' = MeO, 57%
3ib, R2 = 3,4-Me2C6H3 45%
3lb, R2 = 2-naphthyl, 34%
Cl4Ti
O
S
1
O
S
3nb, R2
=
nHex, 52%
-TiCl4
O
O
Scheme 7 One-pot synthesis of 3,4-disubstituted isocoumarins start-
R2
R2
ing from 2-formylbenzoic acids
N
N
H
H
3
R1
R1
D
tapped potential of 3-amino-4-sulfanyl isocoumarins
which, in addition to potentially possessing biological activ-
ities, display notable fluorescence properties (see the Sup-
porting Information for further details).
Scheme 6 A plausible mechanistic pathway
We envisioned developing a one-pot procedure for the
formation of 3-amino-4-sulfanyl isocoumarins 3 starting
directly from 2-formylbenzoic acids 4 and thiols 5. Unfortu-
nately, all our attempts at a multicomponent version of the
reaction failed. The sulfanyl-phthalides 1 were thus pre-
formed at room temperature by mixing the 2-formylbenzo-
ic acid 4 with the thiol 5 in the presence of catalytic
amounts of the Lewis acid and 4 Å molecular sieves. After
one hour, a slight excess of isocyanide 2 was added to the
reaction mixture along with one equivalent of TiCl4. Under
these optimized conditions, the desired 3,4-disubstituted
isocoumarins 3 were isolated in good yields in all the cases
examined (Scheme 7). Albeit sequential, this method allows
a convenient and efficient synthesis of 4-amino-3-thio-
substituted isocoumarins 3 avoiding the tedious isolation of
sulfanyl-phthalides 1.
All reactions were performed under an argon atmosphere and the re-
agents were ordered from commercial suppliers and used without
further purification. Solvents were distilled or purified on activated
alumina columns before use. Isocyanides 2f–h and substituted 2-
formylbenzoic acids 4b and 4c were prepared according to literature
procedures.8d,12 The preparation and characterization of compounds
1a, 1m, 1o, 1p, 3aa, 3ab, 3ad, 3af, 3ma, 3mb and 3ob have previously
been reported.11 Column chromatography was accomplished using
Acros Silica gel 60 (40–63 μm). Melting points were obtained using a
Kofler bench apparatus. 1H, 13C and 19F NMR spectra were obtained
using Bruker AVANCE 300 or 400 spectrometers with CDCl3 as the sol-
vent. High-resolution mass spectrometry was performed using a Jed
JMS-GCmate II instrument.
General Procedure A
To conclude, we have developed an original access to a
large variety of interesting 3,4-hetero-disubstituted isocou-
marin derivatives starting from easily accessible 2-formyl-
benzoic acids, thiols and isocyanides. This straightforward
and operationally simple process enables the synthesis of
isocoumarins with different substitution patterns. In addi-
tion, this method constitutes a new tool to explore the un-
To a stirred solution of 2-formylbenzoic acid 4a–c (1.1 mmol), p-tol-
uenesulfonic acid (8 mg) and MgSO4 (2.0 g) in anhyd toluene (5 mL)
was added the appropriate thiol 5 (1.0 mmol). The mixture was heat-
ed at reflux for 3 h before being cooled to room temperature and fil-
tered through a small pad of silica. After washing with toluene (3 × 20
mL), the solvent was removed under reduced pressure to afford essen-
tially pure racemic 3-sulfanyl-phthalide 1 or, if needed, the residue
was submitted to purification by silica gel flash column chromatogra-
phy.
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E
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Synthesis
General Procedure B
(R/S)-3-(4-tert-Butylphenylthio)isobenzofuran-1(3H)-one (1d)
To a screw-cap vial under an argon atmosphere were sequentially
added thiophthalide 1 (100 mg, 1 equiv), isocyanide 2 (1.2 equiv),
CH2Cl2 (5 mL) and TiCl4 (1 M in CH2Cl2, 1 equiv). The resulting mixture
was stirred at room temperature for 1 h before dropwise addition of
saturated aqueous NaHCO3 (10 mL). After separation of the organic
phase, the aqueous layer was extracted with CH2Cl2 (4 × 15 mL) and
the combined organic extracts washed with H2O (40 mL) and brine
(40 mL) before being dried over MgSO4. After filtration and evapora-
tion of the solvents under reduced pressure, the crude material was
purified by flash column chromatography on silica gel to afford the
desired isocoumarin derivative 3.
Starting from phthalaldehydic acid (4a) (165 mg, 1.1 mmol) and 4-
tert-butylbenzenethiol (5d) (168 μL, 1 mmol) and following the gen-
eral procedure A, 1d was obtained as a white solid (284 mg, 95%
yield); mp 102–104 °C.
1H NMR (400 MHz, CDCl3): δ = 7.71 (d, J = 7.7 Hz, 1 H), 7.65–7.40 (m, 2
H), 7.46–7.34 (m, 3 H), 7.24–7.19 (m, 2 H), 6.61 (s, 1 H), 1.19 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 169.3, 152.5, 146.3, 134.3, 133.7,
130.0, 127.1, 126.4, 126.2, 125.5, 123.5, 87.0, 34.7, 31.3.
HRMS (ESI): m/z [M•]+ calcd for C18H18O2S: 298.1028; found:
298.1033.
(R/S)-3-[(4-Fluorophenyl)thio]isobenzofuran-1(3H)-one (1e)
General Procedure C
Starting from phthalaldehydic acid (4a) (500 mg, 3.3 mmol, 1.1 equiv)
and 4-fluorothiophenol (5e) (320 μL, 3 mmol, 1 equiv) and following
the general procedure A, 1e was obtained as a white solid (443 mg,
57% yield); mp 112–114 °C.
1H NMR (300 MHz, CDCl3): δ = 7.77 (d, J = 7.6 Hz, 1 H), 7.71 (td, J = 7.5,
1.1 Hz, 1 H), 7.64 (dd, J = 7.7, 1.0 Hz, 1 H), 7.50 (t, J = 7.4 Hz, 1 H), 7.48–
7.42 (m, 2 H), 6.96–6.91 (m, 2 H), 6.65 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 169.0, 163.4 (d, JC–F =250.2 Hz), 146.0,
136.7 (d, JC–F = 8.7 Hz), 134.3, 130.0, 126.2, 125.5, 124.6 (d, JC–F = 3.4
Hz), 123.3, 116.2 (d, JC–F = 22.0 Hz), 86.3.
To a screw-cap vial under an argon atmosphere were sequentially
added the 2-carboxybenzaldehyde 4 (1.10 mmol, 1.1 equiv), the ap-
propriate thiol 5 (1.00 mmol, 1.0 equiv), CH2Cl2 (5 mL), activated 4 Å
MS (2.00 g) and TiCl4 (200 μL, 1 M in CH2Cl2, 0.2 equiv). After stirring
the resulting mixture at room temperature for 1 h, isocyanide 2 (1.50
mmol, 1.5 equiv) and TiCl4 (1.00 mL, 1 M in CH2Cl2, 1 equiv) were se-
quentially added. After 1 h, the reaction mixture was poured into sat-
urated aqueous NaHCO3 (20 mL) and the organic layer was separated.
The aqueous phase was then extracted with CH2Cl2 (4 × 20 mL) and
the combined organic extracts washed with H2O (50 mL) and brine
(50 mL) before being dried over MgSO4. After filtration and evapora-
tion of the solvents under reduced pressure, the crude material was
purified by flash column chromatography on silica gel to afford the
desired isocoumarin derivative 3.
19F NMR (300 MHz, CDCl3): δ = –111.2.
HRMS (ESI): m/z [M•]+ calcd for C14H9FO2S: 260.0307; found:
260.0315.
(R/S)-3-(p-Tolylthio)isobenzofuran-1(3H)-one (1b)
(R/S)-3-(4-Bromophenylthio)isobenzofuran-1(3H)-one (1f)
Starting from phthalaldehydic acid (4a) (165 mg, 1.1 mmol) and 4-
methylbenzenethiol (5b) (124 mg, 1 mmol) and following the general
procedure A, 1b was obtained as a white solid (251 mg, 98% yield);
mp 126–128 °C.
Starting from phthalaldehydic acid (4a) (165 mg, 1.1 mmol) and 4-
bromobenzenethiol (5f) (189 mg, 1 mmol) and following the general
procedure A, 1f was obtained as a white solid (313 mg, 98% yield); mp
142–144 °C.
1H NMR (400 MHz, CDCl3): δ = 7.81–7.62 (m, 3 H), 7.49 (t, J = 7.4 Hz, 1
H), 7.39–7.33 (m, 2 H), 7.05 (d, J = 7.9 Hz, 2 H), 6.66 (s, 1 H), 2.29 (s, 3
H).
1H NMR (300 MHz, CDCl3): δ = 7.80 (d, J = 7.6 Hz, 1 H), 7.75–7.67 (m, 1
H), 7.64 (dd, J = 7.6, 0.8 Hz, 1 H), 7.52 (t, J = 7.4 Hz, 1 H), 7.42–7.32 (m,
4 H), 6.68 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 169.3, 146.4, 139.4, 134.3 (2 C), 130.0,
13C NMR (75 MHz, CDCl3): δ = 169.0, 146.0, 135.4, 134.5, 132.4, 130.3,
129.9, 126.4, 125.5, 123.5, 86.8, 21.3.
129.4, 126.4, 125.7, 123.8, 123.4, 86.1.
HRMS (ESI): m/z [M•]+ calcd for C15H12O2S: 256.0558; found:
HRMS (ESI): m/z [M•]+ calcd for C14H9BrO2S: 319.9507; found:
256.0556.
319.9507.
(R/S)-3-[(4-Methoxyphenyl)thio]isobenzofuran-1(3H)-one (1c)
(R/S)-3-(3-Bromophenylthio)isobenzofuran-1(3H)-one (1g)
Starting from phthalaldehydic acid (4a) (400 mg, 2.7 mmol, 1.1 equiv)
and 4-methoxythiophenol (5c) (300 μL, 2.4 mmol, 1 equiv) and fol-
lowing the general procedure A, 1c was obtained as a white solid (498
mg, 76% yield); mp 112–114 °C.
Starting from phthalaldehydic acid (4a) (165 mg, 1.1 mmol) and 3-
bromobenzenethiol (5g) (118 μL, 1 mmol) and following the general
procedure A, 1g was obtained as a white solid (308 mg, 96% yield);
mp 114–116 °C.
1H NMR (300 MHz, CDCl3): δ = 7.73 (d, J = 7.6 Hz, 1 H), 7.71–7.66 (m, 1
H), 7.63 (dd, J = 7.5, 0.7 Hz, 1 H), 7.49–7.44 (m, 1 H), 7.39–7.32 (m, 2
H), 6.75–6.71 (m, 2 H), 6.60 (s, 1 H), 3.74 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 7.7 Hz, 1 H), 7.72 (td, J = 7.6,
1.0 Hz, 1 H), 7.67–7.60 (m, 2 H), 7.53 (t, J = 7.5 Hz, 1 H), 7.49–7.36 (m,
2 H), 7.14 (t, J = 7.9 Hz, 1 H), 6.72 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 169.1, 160.6, 146.3, 136.7, 134.1, 129.8,
13C NMR (101 MHz, CDCl3): δ = 168.9, 145.7, 135.6, 134.5, 132.9,
126.2, 125.3, 123.3, 119.5, 114.4, 86.7, 55.2.
131.9, 131.8, 130.5, 130.4, 126.2, 125.6, 123.5, 122.7, 86.1.
HRMS (ESI): m/z [M•]+ calcd for C15H12O3S: 272.0507; found:
HRMS (ESI): m/z [M•]+ calcd for C14H9BrO2S: 319.9507; found:
272.0508.
319.9508.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–L

F
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Paper
Synthesis
(R/S)-3-(2-Bromophenylthio)isobenzofuran-1(3H)-one (1h)
HRMS (ESI): m/z [M•]+ calcd for C18H12O2S: 292.0558; found:
292.0560.
Starting from phthalaldehydic acid (4a) (165 mg, 1.1 mmol) and 2-
bromobenzenethiol (5h) (120 μL, 1 mmol) and following the general
procedure A, 1h was obtained after crystallization from hexane/tolu-
ene (5:1) as a white solid (134 mg, 42% yield); mp 132–134 °C.
1H NMR (300 MHz, CDCl3): δ = 7.90 (d, J = 7.6 Hz, 1 H), 7.83–7.69 (m, 3
H), 7.64–7.53 (m, 2 H), 7.33 (td, J = 7.7, 1.4 Hz, 1 H), 7.25–7.15 (m, 1
H), 6.83 (s, 1 H).
(R/S)-3-(Naphthalen-2-ylthio)isobenzofuran-1(3H)-one (1l)
Starting from phthalaldehydic acid (4a) (165 mg, 1.1 mmol) and
naphthalene-2-thiol (5l) (160.2 mg, 1.0 mmol) and following the gen-
eral procedure A, 1l was obtained as a white solid (208 mg, 71%
yield); mp 120–122 °C.
1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 1.3 Hz, 1 H), 7.80–7.66 (m, 6
13C NMR (75 MHz, CDCl3): δ = 169.1, 145.6, 134.6, 133.7, 133.52,
H), 7.57–7.44 (m, 4 H), 6.77 (s, 1 H).
133.46, 130.5, 129.8, 128.4, 126.4, 126.3, 125.8, 123.8, 85.7.
13C NMR (101 MHz, CDCl3): δ = 169.2, 146.0, 134.4, 133.4, 133.0,
132.9, 130.1, 130.0, 128.8, 128.0, 127.8, 127.7, 126.9, 126.8, 126.2,
125.5, 123.5, 86.7.
HRMS (ESI): m/z [M•]+ 79Br) and [M•]+ 81Br) calcd for C14H9BrO2S:
( (
319.9507 and 321.9507; found: 319.9509 and 321.9599.
(R/S)-3-(3,4-Dimethylphenylthio)isobenzofuran-1(3H)-one (1i)
HRMS (ESI): m/z [M•]+ calcd for C18H12O2S: 292.0558; found:
292.0568.
Starting from phthalaldehydic acid (4a) (165 mg, 1.1 mmol) and 3,4-
dimethylbenzenethiol (5i) (135 μL, 1.0 mmol) and following the gen-
eral procedure A, 1i was obtained as a white solid (234 mg, 87%
yield); mp 130–132 °C.
1H NMR (400 MHz, CDCl3): δ = 7.71–7.54 (m, 3 H), 7.41 (t, J = 7.4 Hz, 1
H), 7.21–7.11 (m, 2 H), 6.92 (d, J = 7.8 Hz, 1 H), 6.57 (s, 1 H), 2.11 (t, J =
4.5 Hz, 6 H).
(R/S)-3-(Hexylthio)isobenzofuran-1(3H)-one (1n)
Starting from phthalaldehydic acid (4a) (165 mg, 1.1 mmol) and hex-
ane-1-thiol (5n) (141 μL, 1.0 mmol) and following the general proce-
dure A, 1n was obtained as a colorless oil (233 mg, 93% yield).
1H NMR (300 MHz, CDCl3): δ = 7.82 (d, J = 7.5 Hz, 1 H), 7.65 (dd, J =
10.9, 4.1 Hz, 1 H), 7.56–7.43 (m, 2 H), 6.53 (s, 1 H), 2.69–2.44 (m, 2 H),
1.64–1.47 (m, 2 H), 1.40–1.10 (m, 6 H), 0.81 (dd, J = 6.8, 5.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 169.3, 146.3, 137.9, 137.6, 135.1,
134.3, 131.5, 130.3, 130.0, 126.9, 126.3, 125.4, 123.5, 87.0, 19.6 (2 C).
13C NMR (75 MHz, CDCl3): δ = 169.3, 146.8, 134.3, 129.9, 126.2, 125.4,
HRMS (ESI): m/z [M•]+ calcd for C16H14O2S: 270.0715; found:
123.1, 85.0, 31.2, 30.7, 29.5, 28.3, 22.4, 13.9.
270.0719.
HRMS (ESI): m/z [M•]+ calcd for C14H18O2S: 250.1028; found:
(R/S)-3-[(3,4-Dimethoxyphenyl)thio]isobenzofuran-1(3H)-one (1j)
250.1023.
Starting from phthalaldehydic acid (4a) (200 mg, 1.3 mmol) and 3,4-
dimethoxythiophenol (5j) (173 μL, 1.2 mmol) and following the gen-
eral procedure A, then purification of the crude material by flash col-
umn chromatography on silica gel using cyclohexane/ethyl acetate
(7:3) as eluent gave 1j as a white solid (351 mg, 97% yield); mp 119–
121 °C.
(R/S)-3-(Benzylthio)isobenzofuran-1(3H)-one (1q)
Starting from phthalaldehydic acid (4a) (165 mg, 1.1 mmol) and
phenylmethanethiol (5q) (118 μL, 1.0 mmol) and following the gener-
al procedure A, 1q was obtained as a white solid (252 mg, 98% yield);
mp 83–85 °C.
1H NMR (300 MHz, CDCl3): δ = 7.73 (d, J = 7.7 Hz, 1 H), 7.72–7.62 (m, 2
H), 7.50–7.44 (m, 1 H), 7.03 (dd, J = 8.3, 2.1 Hz, 1 H), 6.89 (d, J = 2.1 Hz,
1 H), 6.70 (d, J = 8.3 Hz, 1 H), 6.65 (s, 1 H), 3.82 (s, 3 H), 3.79 (s, 3 H).
1H NMR (300 MHz, CDCl3): δ = 7.80 (d, J = 7.6 Hz, 1 H), 7.57 (td, J = 7.5,
1.1 Hz, 1 H), 7.46 (dd, J = 10.9, 4.0 Hz, 1 H), 7.38 (dd, J = 7.6, 0.8 Hz, 1
H), 7.29–7.14 (m, 5 H), 6.32 (s, 1 H), 3.93 (d, J = 13.2 Hz, 1 H), 3.74 (d,
J = 13.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 169.1, 150.2, 148.7, 146.4, 134.1, 129.8,
13C NMR (75 MHz, CDCl3): δ = 169.3, 146.5, 136.5, 134.3, 130.0, 129.2,
128.7, 127.5, 126.3, 125.6, 123.0, 83.3, 35.0.
128.4, 126.3, 125.4, 123.3, 119.6, 117.7, 111.1, 86.6, 56.0, 55.8.
HRMS (ESI): m/z [M•]+ calcd for C16H14O4S: 302.0613; found:
HRMS (ESI): m/z [M•]+ calcd for C15H12O2S: 256.0558; found:
302.0618.
256.0570.
(R/S)-3-(Naphthalen-1-ylthio)isobenzofuran-1(3H)-one (1k)
Starting from phthalaldehydic acid (4a) (500 mg, 3.3 mmol) and
naphthalene-1-thiol (5k) (420 μL, 3.0 mmol) and following the gener-
al procedure A, then purification of the crude material by flash col-
umn chromatography on silica gel using cyclohexane/ethyl acetate
(9:1) as eluent gave 1k as a white solid (161 mg, 18% yield); mp 103–
105 °C.
(R/S)-Methyl 2-(3-Oxo-1,3-dihydroisobenzofuran-1-ylthio)ace-
tate (1r)
Starting from phthalaldehydic acid (4a) (165 mg, 1.1 mmol) and
methyl 2-mercaptoacetate (5r) (91 μL, 1.0 mmol) and following the
general procedure A, 1q was obtained as colorless oil (186 mg, 78%
yield).
1H NMR (300 MHz, CDCl3): δ = 8.57 (d, J = 8.4 Hz, 1 H), 7.92 (d, J = 7.2
Hz, 1 H), 7.86–7.77 (m, 3 H), 7.74–7.71 (m, 1 H), 7.69–7.59 (m, 2 H),
7.57–7.38 (m, 3 H), 6.74 (s, 1 H).
1H NMR (300 MHz, CDCl3): δ = 7.85 (d, J = 7.0 Hz, 1 H), 7.69 (t, J = 7.5
Hz, 1 H), 7.54 (t, J = 7.2 Hz, 2 H), 6.71 (s, 1 H), 3.67 (d, J = 1.9 Hz, 3 H),
3.46 (dd, J = 15.4, 1.9 Hz, 1 H), 3.25 (d, J = 15.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 169.0, 146.0, 134.1, 134.0, 133.9, 130.1,
130.0, 128.5, 128.0, 127.0, 126.4, 126.1, 125.5, 125.4, 125.3, 123.4,
86.8.
13C NMR (75 MHz, CDCl3): δ = 169.8, 168.9, 145.8, 134.5, 130.3, 126.3,
125.7, 123.2, 83.5, 52.7, 31.6.
HRMS (ESI): m/z [M•]+ calcd for C11H10O4S: 238.0300; found:
238.0310.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–L

G
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Paper
Synthesis
(R/S)-6-Methyl-3-(phenylthio)isobenzofuran-1(3H)-one (1a′)
HRMS (ESI): m/z [M•]+ calcd for C18H15NO4S: 341.0722; found:
341.0710.
Starting from 2-formyl-5-methylbenzoic acid (4b) (271 mg, 1.65
mmol) and thiophenol (5a) (154 μL, 1.5 mmol) and following the gen-
eral procedure A, 1a′ was obtained as a white solid (321 mg, 84%
yield); mp 128–130 °C.
3-(4-Chlorophenylamino)-4-(phenylthio)-1H-isochromen-1-one
(3ag)
1H NMR (300 MHz, CDCl3): δ = 7.50–7.37 (m, 5 H), 7.21–7.13 (m, 3 H),
6.58 (s, 1 H), 2.33 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 169.3, 143.5, 140.6, 135.5, 133.5, 130.8,
129.1, 128.8, 126.5, 125.4, 123.1, 86.5, 21.4.
HRMS (ESI): m/z [M•]+ calcd for C15H12O2S: 256.0558; found:
256.0563.
Starting from 3-(phenylthio)isobenzofuran-1(3H)-one (1a) (100 mg,
0.41 mmol), 4-chlorophenylisocyanide (2g) (68.5 mg, 0.50 mmol), Ti-
Cl4 (410 μL, 1 M in CH2Cl2, 0.41 mmol) and following the general pro-
cedure B, then purification of the crude material by flash column
chromatography on silica gel using cyclohexane/ethyl acetate (98:2)
as eluent gave 3ag as a yellow solid (123 mg, 79% yield); mp 130–
132 °C.
1H NMR (300 MHz, CDCl3): δ = 8.09 (dd, J = 8.0, 0.9 Hz, 1 H), 7.62 (d,
J = 8.3 Hz, 2 H), 7.55–7.40 (m, 1 H), 7.24–7.02 (m, 10 H).
13C NMR (75 MHz, CDCl3): δ = 159.5, 156.1, 141.0, 136.0, 135.9, 135.2,
130.3, 129.58, 129.53, 129.48, 126.2, 125.8, 124.8, 123.0, 122.1, 116.4,
80.0.
(R/S)-6-Methoxy-3-(naphthalen-2-ylthio)isobenzofuran-1(3H)-
one (1l′′)
Starting from 2-formyl-5-methoxybenzoic acid (4c) (297 mg, 1.65
mmol) and naphthalene-2-thiol (5l) (240 mg, 1.5 mmol) and follow-
ing the general procedure A, 1l′′ was obtained as a white solid (466
mg, 96% yield); mp 130–132 °C.
HRMS (ESI): m/z [M•]+ calcd for C21H14ClNO2S: 379.0434; found:
379.0452.
1H NMR (300 MHz, CDCl3): δ = 8.06 (d, J = 1.2 Hz, 1 H), 7.84–7.70 (m, 3
H), 7.60–7.45 (m, 4 H), 7.27–7.18 (m, 2 H), 6.74 (s, 1 H), 3.80 (s, 3 H).
3-(2-Methoxyphenylamino)-4-(phenylthio)-1H-isochromen-1-
one (3ah)
13C NMR (75 MHz, CDCl3): δ = 169.2, 161.4, 138.2, 133.5, 132.9, 132.7,
129.9, 128.7, 128.5, 127.8, 127.7, 126.9, 126.7, 124.3, 123.1, 107.4,
86.8, 55.8.
HRMS (ESI): m/z [M•]+ calcd for C19H14O3S: 322.0664; found:
322.0662.
Starting from 3-(phenylthio)isobenzofuran-1(3H)-one (1a) (100 mg,
0.41 mmol), 2-methoxyphenylisocyanide (2h) (66.3 mg, 0.50 mmol),
TiCl4 (410 μL, 1 M in CH2Cl2, 0.41 mmol) and following the general
procedure B, then purification of the crude material by flash column
chromatography on silica gel using cyclohexane/ethyl acetate (98:2)
as eluent gave 3ah as a yellow solid (21.9 mg, 14% yield); mp 100–
102 °C.
1H NMR (300 MHz, CDCl3): δ = 8.46 (s, 1 H), 8.24–8.19 (m, 1 H), 7.97–
7.92 (m, 1 H), 7.81–7.76 (m, 1 H), 7.65–7.60 (m, 1 H), 7.31–7.14 (m, 6
H), 7.10–7.00 (m, 2 H), 6.92–6.87 (m, 1 H), 3.83 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 159.9, 156.7, 149.0, 141.7, 135.8, 130.2,
129.3, 127.4, 126.4, 126.0, 124.3, 123.7, 122.9, 121.5, 119.7, 116.0,
110.7, 80.4, 56.1.
HRMS (ESI): m/z [M•]+ calcd for C22H17NO3S: 375.0929; found:
375.0929.
3-(Pentylamino)-4-(phenylthio)-1H-isochromen-1-one (3ac)
Starting from 3-(phenylthio)isobenzofuran-1(3H)-one (1a) (100 mg,
0.41 mmol), 1-isocyanopentane (2c) (63 μL, 0.50 mmol), TiCl4 (410
μL, 1 M in CH2Cl2, 0.41 mmol) and following the general procedure B,
then purification of the crude material by flash column chromatogra-
phy on silica gel using cyclohexane/ethyl acetate (98:2) as eluent gave
3ac as a yellow solid (121 mg, 87% yield); mp 102–104 °C.
1H NMR (300 MHz, CDCl3): δ = 8.08–7.96 (m, 1 H), 7.50 (dd, J = 8.2, 0.5
Hz, 1 H), 7.45–7.35 (m, 1 H), 7.16–6.96 (m, 6 H), 5.73 (t, J = 5.9 Hz, 1
H), 3.31 (m, 2 H), 1.52–1.40 (m, 2 H), 1.25–1.11 (m, 4 H), 0.76 (t, J = 6.9
Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 160.5, 159.7, 142.3, 136.1, 135.6, 130.0,
129.2, 125.6, 125.5, 123.2, 121.9, 114.9, 75.5, 42.0, 29.9, 28.8, 22.4,
14.0.
HRMS (ESI): m/z [M•]+ calcd for C20H21NO2S: 339.1293; found:
339.1306.
3-(Cyclohexylamino)-4-(p-tolylthio)-1H-isochromen-1-one (3bb)
Starting from 3-(p-tolylthio)isobenzofuran-1(3H)-one (1b) (100 mg,
0.39 mmol), cyclohexylisocyanide (2b) (58 μL, 0.47 mmol), TiCl4 (390
μL, 1 M in CH2Cl2, 0.39 mmol) and following the general procedure B,
then purification of the crude material by flash column chromatogra-
phy on silica gel using cyclohexane/ethyl acetate (9:1) as eluent gave
3bb as a yellow solid (98 mg, 69% yield). Starting from 4-methylben-
zenethiol (5b) (1.0 mmol) and following general procedure C, 3bb
was obtained as a white solid (204 mg, 56% yield); mp 142–144 °C.
1H NMR (300 MHz, CDCl3): δ = 8.11 (d, J = 7.9 Hz, 1 H), 7.60 (d, J = 8.1
Hz, 1 H), 7.50 (t, J = 7.6 Hz, 1 H), 7.11 (t, J = 7.5 Hz, 1 H), 7.07–6.98 (m,
4 H), 5.72 (d, J = 8.4 Hz, 1 H), 3.92–3.69 (m, 1 H), 2.27 (s, 3 H), 1.99–
1.96 (m, 2 H), 1.77–1.53 (m, 3 H), 1.38–1.34 (m, 2 H), 1.27–1.14 (m, 3
H).
Methyl 2-[1-Oxo-4-(phenylthio)-1H-isochromen-3-ylamino]ace-
tate (3ae)
Starting from 3-(phenylthio)isobenzofuran-1(3H)-one (1a) (50 mg,
0.21 mmol), methyl 2-isocyanoacetate (2e) (23 μL, 0.25 mmol), TiCl4
(210 μL, 1 M in CH2Cl2, 0.21 mmol) and following the general proce-
dure B, then purification of the crude material by flash column chro-
matography on silica gel using cyclohexane/ethyl acetate (98:2) as
eluent gave 3ae as a pale yellow solid (49.3 mg, 70% yield); mp 136–
138 °C.
1H NMR (300 MHz, CDCl3): δ = 8.17–8.11 (m, 1 H), 7.68–7.63 (m, 1 H),
7.60–7.50 (m, 1 H), 7.25–7.09 (m, 6 H), 6.23 (t, J = 5.8 Hz, 1 H), 4.20 (d,
J = 6.0 Hz, 2 H), 3.76 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 160.6, 159.0, 142.2, 135.4, 135.3, 132.3,
129.9, 125.5, 123.0, 121.9, 114.8, 76.2, 50.6, 33.7, 25.3, 24.6, 20.8.
HRMS (ESI): m/z [M•]+ calcd for C22H23NO2S: 365.1449; found:
365.1442.
13C NMR (75 MHz, CDCl3): δ = 170.1, 160.1, 158.6, 141.7, 135.8, 130.1,
129.3, 125.8 (2 C), 124.0, 122.4, 115.6, 78.0, 52.6, 43.3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–L

H
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Paper
Synthesis
3-(Cyclohexylamino)-4-[(4-methoxyphenyl)thio]-1H-isochromen-
HRMS (ESI): m/z [M•]+ calcd for C21H20FNO2S: 369.1199; found:
1-one (3cb)
369.1207.
Starting from 3-[(4-methoxyphenyl)thio]isobenzofuran-1(3H)-one
(1c) (100 mg, 0.37 mmol), cyclohexylisocyanide (2b) (55 μL, 0.44
mmol), TiCl4 (370 μL, 1 M in CH2Cl2, 0.37 mmol) and following the
general procedure B, then purification of the crude material by flash
column chromatography on silica gel using cyclohexane/ethyl acetate
(95:5) as eluent gave 3cb as a yellow solid (91 mg, 65% yield); mp
135–137 °C.
1H NMR (300 MHz, CDCl3): δ = 8.11 (dd, J = 8.0, 1.4 Hz, 1 H), 7.70–7.59
(m, 1 H), 7.60–7.47 (m, 1 H), 7.46–7.33 (m, 1 H), 7.16–7.06 (m, 2 H),
6.87–6.77 (m, 2 H), 5.75 (d, J = 8.5 Hz, 1 H), 3.81–3.80 (m, 1 H), 3.75 (s,
3 H), 1.98 (d, J = 12.1 Hz, 2 H), 1.74–1.60 (m, 3 H), 1.43–1.35 (m, 2 H),
1.28–1.16 (m, 3 H).
4-(4-Bromophenylthio)-3-(cyclohexylamino)-1H-isochromen-1-
one (3fb)
Starting from 3-(4-bromophenylthio)isobenzofuran-1(3H)-one (1f)
(100 mg, 0.31 mmol), cyclohexylisocyanide (2b) (47 μL, 0.37 mmol),
TiCl4 (310 μL, 1 M in CH2Cl2, 0.31 mmol) and following the general
procedure B, then purification of the crude material by flash column
chromatography on silica gel using cyclohexane/ethyl acetate (98:2)
as eluent gave 3fb as a yellow solid (113 mg, 84% yield); mp 150–
152 °C.
1H NMR (300 MHz, CDCl3): δ = 8.16–8.05 (m, 1 H), 7.55–7.49 (m, 2 H),
7.35–7.28 (m, 2 H), 7.16–7.09 (m, 1 H), 7.00–6.92 (m, 2 H), 5.66 (d, J =
8.5 Hz, 1 H), 3.90–3.72 (m, 1 H), 2.03–1.91 (m, 2 H), 1.77–1.55 (m, 3
H), 1.48–1.11 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 159.0, 158.2, 142.3, 135.5, 132.7, 129.9,
127.5, 126.6, 123.0, 122.0, 114.9, 114.6, 55.4, 50.6, 33.8, 25.4, 24.6.
13C NMR (75 MHz, CDCl3): δ = 160.4, 159.3, 141.9, 135.7, 135.4, 132.2,
HRMS (ESI): m/z [M•]+ calcd for C22H23NO3S: 381.1399; found:
130.1, 127.0, 123.3, 121.8, 119.2, 115.0, 75.1, 50.8, 33.8, 25.4, 24.7.
381.1393.
HRMS (ESI): m/z [M•]+ calcd for C21H20BrNO2S: 429.0398; found:
4-{[4-(tert-Butyl)phenyl]thio}-3-(cyclohexylamino)-1H-iso-
429.0411.
chromen-1-one (3db)
Starting from 3-(4-tert-butylphenylthio)isobenzofuran-1(3H)-one
(1d) (100 mg, 0.34 mmol), cyclohexylisocyanide (2b) (50 μL, 0.40
mmol), TiCl4 (340 μL, 1 M in CH2Cl2, 0.34 mmol) and following the
general procedure B, then purification of the crude material by flash
column chromatography on silica gel using cyclohexane/ethyl acetate
(95:5) as eluent gave 3db as a yellow solid (105 mg, 76% yield); mp
109–111 °C.
1H NMR (300 MHz, CDCl3): δ = 8.12 (dd, J = 8.0, 1.0 Hz, 1 H), 7.63 (dd,
J = 8.2, 0.5 Hz, 1 H), 7.55–7.45 (m, 1 H), 7.27–7.23 (m, 2 H), 7.13 (t, J =
7.5 Hz, 1 H), 7.06 (d, J = 8.4 Hz, 2 H), 5.72 (d, J = 8.5 Hz, 1 H), 3.91–3.74
(m, 1 H), 2.02–1.92 (m, 2 H), 1.74–1.68 (m, 2 H), 1.64–1.57 (m, 1 H),
1.45–1.34 (m, 2 H), 1.27 (s, 9 H), 1.24–1.15 (m, 3 H).
4-(3-Bromophenylthio)-3-(cyclohexylamino)-1H-isochromen-1-
one (3gb)
Starting from 3-(3-bromophenylthio)isobenzofuran-1(3H)-one (1g)
(100 mg, 0.31 mmol), cyclohexylisocyanide (2b) (46 μL, 0.37 mmol),
TiCl4 (310 μL, 1 M in CH2Cl2, 0.31 mmol) and following the general
procedure B, then purification of the crude material by flash column
chromatography on silica gel using cyclohexane/ethyl acetate (98:2)
as eluent gave 3gb as a yellow solid (123 mg, 92% yield); mp 108–
110 °C.
1H NMR (300 MHz, CDCl3): δ = 8.13 (d, J = 7.9 Hz, 1 H), 7.64–7.50 (m, 2
H), 7.28–7.21 (m, 2 H), 7.20–7.04 (m, 2 H), 7.04–6.95 (m, 1 H), 5.62 (d,
J = 8.6 Hz, 1 H), 3.91–3.75 (m, 1 H), 2.00–1.95 (m, 2 H), 1.78–1.57 (m,
3 H), 1.50–1.31 (m, 2 H), 1.31–1.13 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 160.6, 159.0, 148.7, 142.3, 135.5, 132.4,
129.9, 126.2, 125.3, 123.0, 122.1, 114.8, 76.3, 50.6, 34.4, 33.7, 31.2,
25.3, 24.6.
13C NMR (75 MHz, CDCl3): δ = 160.4, 159.2, 141.8, 138.5, 135.7, 130.5,
130.1, 128.6, 127.9, 123.7, 123.3, 123.2, 121.7, 114.9, 74.6, 50.7, 33.7,
25.3, 24.6.
HRMS (ESI): m/z [M•]+ calcd for C25H29NO2S: 407.1919; found:
HRMS (ESI): m/z [M•]+ calcd for C21H20BrNO2S: 429.0398; found:
407.1933.
429.0409.
3-(Cyclohexylamino)-4-[(4-fluorophenyl)thio]-1H-isochromen-1-
one (3eb)
4-(2-Bromophenylthio)-3-(cyclohexylamino)-1H-isochromen-1-
Starting from 3-[(4-fluorophenyl)thio]isobenzofuran-1(3H)-one (1e)
(100 mg, 0.38 mmol), cyclohexylisocyanide (2b) (57 μl, 0.46 mmol),
TiCl4 (380 μL, 1 M in CH2Cl2, 0.38 mmol) and following the general
procedure B, then purification of the crude material by flash column
chromatography on silica gel using cyclohexane/ethyl acetate (9:1) as
eluent gave 3eb as a yellow solid (96 mg, 68% yield); mp 140–142 °C.
1H NMR (300 MHz, CDCl3): δ = 8.18–8.04 (m, 1 H), 7.61–7.56 (m, 1 H),
7.55–7.51 (m, 1 H), 7.15–7.12 (m, 1 H), 7.11–7.05 (m, 2 H), 6.98–6.90
(m, 2 H), 5.69 (d, J = 8.4 Hz, 1 H), 3.87–3.74 (m, 1 H), 1.97 (dd, J = 12.6,
3.5 Hz, 2 H), 1.74–1.66 (m, 2 H), 1.65–1.58 (m, 1 H), 1.46–1.35 (m, 2
H), 1.26–1.15 (m, 3 H).
one (3hb)
Starting from 3-(2-bromophenylthio)isobenzofuran-1(3H)-one (1h)
(100 mg, 0.31 mmol), cyclohexylisocyanide (2b) (47 μL, 0.37 mmol),
TiCl4 (310 μL, 1 M in CH2Cl2, 0.31 mmol) and following the general
procedure B, then purification of the crude material by flash column
chromatography on silica gel using cyclohexane/ethyl acetate (98:2)
as eluent gave 3hb as a yellow crystalline solid (110 mg, 82% yield);
mp 148–150 °C.
1H NMR (300 MHz, CDCl3): δ = 8.16–8.10 (m, 1 H), 7.53 (m, 3 H), 7.18–
7.06 (m, 2 H), 7.03–6.95 (m, 1 H), 6.74 (dd, J = 7.9, 1.6 Hz, 1 H), 5.62 (d,
J = 8.5 Hz, 1 H), 3.89–3.75 (m, 1 H), 1.96 (dd, J = 12.2, 3.1 Hz, 2 H),
1.78–1.56 (m, 3 H), 1.42–1.13 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 161.2 (d, JC–F = 244.0 Hz), 160.4, 159.1,
142.0, 135.6, 130.9 (d, JC–F = 3.1 Hz), 130.0, 127.1 (d, JC–F = 7.8 Hz),
123.2, 121.7, 116.3 (d, JC–F = 22.1 Hz), 114.9, 76.1, 50.6, 33.7, 25.3,
24.6.
13C NMR (75 MHz, CDCl3): δ = 160.4, 159.3, 141.9, 136.8, 135.7, 133.2,
130.1, 128.0, 126.7, 125.5, 123.4, 121.9, 121.0, 115.1, 74.9, 50.9, 33.8,
25.4, 24.8.
19F NMR (300 MHz, CDCl3 ): δ = –117.1.
HRMS (ESI): m/z [M•]+ (79Br) and [M•]+ (81Br) calcd for C21H20BrNO2S:
429.0398 and 431.0398; found: 429.0407 and 431.0359.
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S. Ponra et al.
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Synthesis
3-(Cyclohexylamino)-4-[(3,4-dimethylphenyl)thio]-1H-iso-
HRMS (ESI): m/z [M•]+ calcd for C22H23NO2S: 365.1449; found:
chromen-1-one (3ib)
365.1461.
Starting from 3-(3,4-dimethylphenylthio)isobenzofuran-1(3H)-one
(1i) (100 mg, 0.37 mmol), cyclohexylisocyanide (2b) (55 μL, 0.44
mmol), TiCl4 (370 μL, 1 M in CH2Cl2, 0.37 mmol) and following the
general procedure B, then purification of the crude material by flash
column chromatography on silica gel using cyclohexane/ethyl acetate
(95:5) as eluent gave 3ib as a yellow solid (125 mg, 89% yield). Start-
ing from 3,4-dimethylbenzenethiol (5i) (1.0 mmol) and following
general procedure C, 3ib was obtained as a yellow solid (169 mg, 45%
yield); mp 128–130 °C.
1H NMR (300 MHz, CDCl3): δ = 8.19–8.06 (m, 1 H), 7.63 (d, J = 8.1 Hz, 1
H), 7.55–7.46 (m, 1 H), 7.16–7.07 (m, 1 H), 6.97 (dd, J = 11.9, 4.7 Hz, 2
H), 6.85 (dd, J = 7.9, 1.9 Hz, 1 H), 5.76 (d, J = 8.5 Hz, 1 H), 3.91–3.77 (m,
1 H), 2.19 (s, 6 H), 2.00 (dd, J = 12.2, 3.0 Hz, 2 H), 1.79–1.57 (m, 3 H),
1.51–1.14 (m, 5 H).
3-(Cyclohexylamino)-7-methoxy-4-(naphthalen-2-ylthio)-1H-iso-
chromen-1-one (3l′′b)
Starting from 6-methoxy-3-(naphthalen-2-ylthio)isobenzofuran-
1(3H)-one (1l′′) (100 mg, 0.31 mmol), cyclohexylisocyanide (2a) (46
μL, 0.37 mmol), TiCl4 (310 μL, 1 M in CH2Cl2, 0.31 mmol) and follow-
ing the general procedure B, then purification of the crude material
by flash column chromatography on silica gel using cyclohexane/ethyl
acetate (99:1) as eluent gave 3l′′b as a yellow solid (114 mg, 86%
yield); mp 132–134 °C.
1H NMR (300 MHz, CDCl3): δ = 7.65 (dd, J = 11.8, 8.0 Hz, 2 H), 7.58–
7.44 (m, 3 H), 7.41–7.26 (m, 3 H), 7.17 (dd, J = 8.2, 2.2 Hz, 1 H), 7.06
(dd, J = 9.0, 2.7 Hz, 1 H), 5.49 (d, J = 8.6 Hz, 1 H), 3.83–3.63 (m, 4 H),
1.89 (dd, J = 12.3, 3.2 Hz, 2 H), 1.68–1.43 (m, 3 H), 1.40–0.96 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 160.6, 159.1, 142.4, 137.6, 135.5, 134.2,
132.6, 130.4, 129.9, 126.9, 123.0 (2 C), 122.1, 115.0, 76.5, 50.7, 33.8,
25.4, 24.7, 19.8, 19.2.
HRMS (ESI): m/z [M•]+ calcd for C23H25NO2S: 379.1606; found:
379.1601.
13C NMR (75 MHz, CDCl3): δ = 160.8, 158.3, 156.3, 136.4, 134.0, 133.7,
131.8, 129.0, 127.9, 127.0, 126.8, 126.0, 125.6, 124.1, 124.0, 123.2,
115.7, 110.0, 76.0, 55.8, 50.9, 33.9, 25.5, 24.8.
HRMS (ESI): m/z [M•]+ calcd for C26H25NO3S: 431.1555; found:
431.1572.
3-(Cyclohexylamino)-4-[(3,4-dimethoxyphenyl)thio]-1H-iso-
chromen-1-one (3jb)
3-(Cyclohexylamino)-4-(naphthalen-1-ylthio)-1H-isochromen-1-
one (3kb)
Starting from 3-(3,4-dimethoxyphenylthio)isobenzofuran-1(3H)-one
(1j) (100 mg, 0.33 mmol), cyclohexylisocyanide (2b) (49 μL, 0.40
mmol), TiCl4 (330 μL, 1 M in CH2Cl2, 0.33 mmol) and following the
general procedure B, then purification of the crude material by flash
column chromatography on silica gel using cyclohexane/ethyl acetate
(8:2) as eluent gave 3jb as a yellow pasty residue (75 mg, 55% yield).
1H NMR (300 MHz, CDCl3): δ = 8.11 (dd, J = 7.9, 1.0 Hz, 1 H), 7.63 (d,
J = 7.9 Hz, 1 H), 7.53 (m, 1 H), 7.12 (m, 1 H), 6.73 (d, J = 8.4 Hz, 1 H),
6.72 (d, J = 2.1 Hz, 1 H), 6.64 (dd, J = 8.4, 2.1 Hz, 1 H), 5.75 (d, J = 8.6 Hz,
1 H), 3.86–3.81 (m, 1 H), 3.81 (s, 3 H), 3.78 (s, 3 H), 2.02–1.94 (m, 2 H),
1.76–1.67 (m, 2 H), 1.66–1.58 (m, 1 H), 1.49–1.32 (m, 2 H), 1.30–1.12
(m, 3 H).
Starting from 3-(naphthalen-2-ylthio)isobenzofuran-1(3H)-one (1k)
(90 mg, 0.31 mmol), cyclohexylisocyanide (2b) (46 μl, 0.37 mmol),
TiCl4 (310 μL, 1 M in CH2Cl2, 0.31 mmol) and following the general
procedure B, then purification of the crude material by flash column
chromatography on silica gel using cyclohexane/ethyl acetate (95:5)
as eluent gave 3kb as a yellow solid (80 mg, 68% yield); mp 135–
137 °C.
1H NMR (300 MHz, CDCl3): δ = 8.38 (d, J = 8.4 Hz, 1 H), 8.16 (d, J = 8.0
Hz, 1 H), 7.89 (d, J = 7.6 Hz, 1 H), 7.66–7.60 (m, 2 H), 7.59–7.53 (m, 2
H), 7.51–7.44 (m, 1 H), 7.28–7.24 (m, 1 H), 7.16–7.11 (m, 1 H), 6.96 (d,
J = 7.4 Hz, 1 H), 5.67 (d, J = 8.5 Hz, 1 H), 3.89–3.78 (m, 1 H), 2.01–1.91
(m, 2 H), 1.73–1.64 (m, 2 H), 1.63–1.56 (m, 1 H), 1.43–1.32 (m, 2 H),
1.22–1.08 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 160.6, 159.0, 149.5, 147.6, 142.2, 135.5,
129.9, 127.0, 123.1, 121.9, 118.0, 114.8, 112.0, 109.6, 77.0, 56.0, 55.9,
50.6, 33.7, 25.3, 24.6.
13C NMR (75 MHz, CDCl3): δ = 160.6, 159.2, 142.1, 135.6, 134.0, 132.3,
130.9, 130.0, 128.7, 126.3, 126.2, 125.9, 125.6, 123.5, 123.2, 122.0,
121.0, 115.1, 74.0, 50.7, 33.7, 25.3, 24.6.
HRMS (ESI): m/z [M•]+ calcd for C23H25NO4S: 411.1504; found:
HRMS (ESI): m/z [M•]+ calcd for C25H23NO2S: 401.1449; found:
411.1515.
401.1450.
3-(Cyclohexylamino)-7-methyl-4-(phenylthio)-1H-isochromen-1-
one (3a′b)
3-(Cyclohexylamino)-4-(naphthalen-2-ylthio)-1H-isochromen-1-
Starting from 6-methyl-3-(phenylthio)isobenzofuran-1(3H)-one (1a′)
(100 mg, 0.39 mmol), cyclohexylisocyanide (2b) (58 μL, 0.47 mmol),
TiCl4 (390 μL, 1 M in CH2Cl2, 0.39 mmol) and following the general
procedure B, then purification of the crude material by flash column
chromatography on silica gel using cyclohexane/ethyl acetate (99:1)
as eluent gave 3a′b as a yellow crystalline solid (132 mg, 93% yield);
mp 126–128 °C.
1H NMR (300 MHz, CDCl3): δ = 7.93 (s, 1 H), 7.50 (d, J = 8.3 Hz, 1 H),
7.35 (dd, J = 8.3, 1.7 Hz, 1 H), 7.28–7.17 (m, 2 H), 7.11 (dd, J = 7.2, 5.4
Hz, 3 H), 5.60 (d, J = 8.5 Hz, 1 H), 3.81 (qd, J = 10.2, 5.1 Hz, 1 H), 2.35 (s,
3 H), 1.97 (dd, J = 12.4, 3.1 Hz, 2 H), 1.76–1.55 (m, 3 H), 1.48–1.08 (m,
5 H).
one (3lb)
Starting from 3-(naphthalen-2-ylthio)isobenzofuran-1(3H)-one (1l)
(100 mg, 0.34 mmol), cyclohexylisocyanide (2b) (51 μL, 0.41 mmol),
TiCl4 (340 μL, 1 M in CH2Cl2, 0.34 mmol) and following the general
procedure B, then purification of the crude material by flash column
chromatography on silica gel using cyclohexane/ethyl acetate (98:2)
as eluent gave 3lb as a yellow solid (115 mg, 84% yield). Starting from
naphthalene-2-thiol (5l) (1.0 mmol) and following general procedure
C, 3lb was obtained as a yellow solid (137 mg, 34% yield); mp 134–
136 °C.
1H NMR (400 MHz, CDCl3): δ = 8.02 (dd, J = 8.0, 1.0 Hz, 1 H), 7.61 (dd,
J = 13.4, 8.2 Hz, 2 H), 7.51 (d, J = 8.6 Hz, 2 H), 7.39–7.22 (m, 4 H), 7.15
(dd, J = 8.6, 1.9 Hz, 1 H), 7.02–6.95 (m, 1 H), 5.64 (d, J = 8.5 Hz, 1 H),
3.77–3.65 (m, 1 H), 1.90–1.80 (m, 2 H), 1.61–1.41 (m, 3 H), 1.33–0.92
(m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 160.9, 158.8, 139.9, 137.2, 136.3, 133.1,
129.6, 129.3, 125.6, 125.5, 122.2, 115.0, 75.9, 50.8, 33.9, 25.5, 24.8,
20.9.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–L

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S. Ponra et al.
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Synthesis
13C NMR (101 MHz, CDCl3): δ = 160.7, 159.2, 142.2, 135.6, 133.9,
133.4, 131.7, 130.0, 128.9, 127.8, 126.9, 126.7, 125.5, 124.0, 123.2,
123.0, 122.0, 115.0, 75.7, 50.7, 33.7, 25.3, 24.7.
HRMS (ESI): m/z [M•]+ calcd for C18H21NO4S: 347.1191; found:
347.1176.
HRMS (ESI): m/z [M•]+ calcd for C25H23NO2S: 401.1449; found:
3-(Benzylamino)-4-(cyclohexylthio)-1H-isochromen-1-one (3od)
401.1463.
Starting from 3-(cyclohexylthio)isobenzofuran-1(3H)-one (1o) (100
mg, 0.40 mmol), benzylisocyanide (2d) (59 μL, 0.48 mmol), TiCl4 (400
μL, 1 M in CH2Cl2, 0.40 mmol) and following the general procedure B,
then purification of the crude material by flash column chromatogra-
phy on silica gel using cyclohexane/ethyl acetate (98:2) as eluent gave
3od as a yellow solid (81 mg, 55% yield); mp 128–130 °C.
1H NMR (300 MHz, CDCl3): δ = 8.00 (dd, J = 8.0, 0.9 Hz, 1 H), 7.71 (d,
J = 8.2 Hz, 1 H), 7.53–7.40 (m, 1 H), 7.30–7.15 (m, 5 H), 7.10–7.02 (m,
1 H), 6.14 (t, J = 6.2 Hz, 1 H), 4.50 (d, J = 6.3 Hz, 2 H), 2.69–2.57 (m, 1
H), 1.83–1.72 (m, 2 H), 1.67–1.38 (m, 3 H), 1.29–1.00 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 160.5, 158.9, 143.0, 138.3, 135.2, 130.0,
128.9, 127.8, 127.7, 123.1, 122.6, 115.3, 79.2, 47.1, 46.0, 33.6, 26.2,
25.7.
HRMS (ESI): m/z [M•]+ calcd for C22H23NO2S: 365.1449; found:
365.1450.
3-(Cyclohexylamino)-4-(hexylthio)-1H-isochromen-1-one (3nb)
Starting from 3-(hexylthio)isobenzofuran-1(3H)-one (1n) (100 mg,
0.40 mmol), cyclohexylisocyanide (2b) (60 μL, 0.48 mmol), TiCl4 (400
μL, 1 M in CH2Cl2, 0.4 mmol) and following the general procedure B,
then purification of the crude material by flash column chromatogra-
phy on silica gel using cyclohexane/ethyl acetate (98:2) as eluent gave
3nb as a yellow solid (133.8 mg, 93% yield). Starting from hexane-1-
thiol (5n) (1.0 mmol) and following general procedure C, 3nb was ob-
tained as a yellow solid (187 mg, 52% yield); mp 58–60 °C.
1H NMR (300 MHz, CDCl3): δ = 8.09–8.05 (m, 1 H), 7.79–7.71 (m, 1 H),
7.60–7.55 (m, 1 H), 7.12–7.07 (m, 1 H), 5.81 (d, J = 8.6 Hz, 1 H), 3.86–
3.69 (m, 1 H), 2.57–2.48 (m, 2 H), 2.07–1.95 (m, 2 H), 1.82–1.15 (m, 16
H), 0.86 (t, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 160.9, 158.6, 142.8, 135.3, 130.1, 122.7,
122.0, 115.0, 78.9, 50.6, 34.8, 34.0, 31.5, 29.8, 28.7, 25.6, 24.8, 22.6,
14.1.
HRMS (ESI): m/z [M•]+ calcd for C21H29NO2S: 359.1919; found:
359.1929.
4-(Benzylthio)-3-(cyclohexylamino)-1H-isochromen-1-one (3qb)
Starting from 3-(benzylthio)isobenzofuran-1(3H)-one (1q) (100 mg,
0.39 mmol), cyclohexylisocyanide (2b) (58 μL, 0.47 mmol), TiCl4
(390μL, 1 M in CH2Cl2, 1.0 equiv) and following the general procedure
B, then purification of the crude material by flash column chromatog-
raphy on silica gel using cyclohexane/ethyl acetate (98:2) as eluent
gave 3qb as a yellow sticky gum (100 mg, 70% yield).
4-(tert-Butylthio)-3-(cyclohexylamino)-1H-isochromen-1-one
(3pb)
Starting from 3-(tert-butylthio)isobenzofuran-1(3H)-one (1p) (100
mg, 0.45 mmol), cyclohexylisocyanide (2b) (67 μL, 0.54 mmol), TiCl4
(450 μL, 1 M in CH2Cl2, 0.45 mmol) and following the general proce-
dure B, then purification of the crude material by flash column chro-
matography on silica gel using cyclohexane/ethyl acetate (98:2) as
eluent gave 3pb as a yellow sticky gum (23.7 mg, 16% yield).
1H NMR (300 MHz, CDCl3): δ = 8.08–8.03 (m, 1 H), 7.87–7.82 (m, 1 H),
7.60–7.40 (m, 1 H), 7.10–7.04 (m, 1 H), 5.98 (d, J = 8.5 Hz, 1 H), 3.87–
3.71 (m, 1 H), 2.00 (d, J = 4.1 Hz, 2 H), 1.77–1.61 (m, 4 H), 1.54–1.18
(m, 13 H).
1H NMR (300 MHz, CDCl3): δ = 8.13–8.05 (m, 1 H), 7.75–7.69 (m, 1 H),
7.52–7.65 (m, 1 H), 7.25–7.17 (m, 3 H), 7.14–7.04 (m, 3 H), 5.41 (d, J =
8.3 Hz, 1 H), 3.67 (s, 2 H), 3.57–3.44 (m, 1 H), 1.75–1.50 (m, 5 H),
1.39–0.84 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 160.7, 159.2, 142.6, 138.5, 135.4, 130.1,
128.9, 128.6, 127.2, 122.7, 121.7, 114.8, 77.1, 50.3, 38.6, 33.6, 25.5,
24.7.
HRMS (APPI): m/z [M•]+ calcd for C22H23NO2S: 365.1449; found:
365.1436.
13C NMR (75 MHz, CDCl3): δ = 160.9, 159.9, 144.3, 134.9, 129.8, 123.2,
122.6, 114.6, 50.6, 49.9, 34.2, 33.9, 31.5, 25.6, 24.9.
HRMS (ESI): m/z [M•]+ calcd for C19H25NO2S: 331.1606; found:
331.1617.
3-(Pentylamino)-4-(p-tolylthio)-1H-isochromen-1-one (3bc)
Starting from 2-carboxybenzaldehyde (4a) (165 mg, 1.1 mmol), 4-
methylbenzenethiol (5b) (124 mg, 1.0 mmol), 1-pentylisocyanide
(2c) (189 mg, 1.5 mmol), TiCl4 (1.2 mL, 1 M in CH2Cl2, 1.2 mmol) and
following the general procedure C, then purification of the crude ma-
terial by flash column chromatography on silica gel using petroleum
ether/ethyl acetate (95:5) as eluent gave 3bc as a yellow pasty residue
(257 mg, 73% yield).
Methyl 2-[3-(Cyclohexylamino)-1-oxo-1H-isochromen-4-
ylthio]acetate (3rb)
Starting
from
methyl
2-(3-oxo-1,3-dihydroisobenzofuran-1-
ylthio)acetate (1r) (100 mg, 0.42 mmol), cyclohexylisocyanide (2b)
(63 μL, 0.50 mmol), TiCl4 (420 μL, 1 M in CH2Cl2, 0.42 mmol) and fol-
lowing the general procedure B, then purification of the crude mate-
rial by flash column chromatography on silica gel using cyclohex-
ane/ethyl acetate (98:2) as eluent gave 3rb as an orange viscous liquid
(34.6 mg, 24% yield).
1H NMR (300 MHz, CDCl3): δ = 8.10–8.04 (m, 1 H), 7.72–7.69 (m, 1 H),
7.65–7.50 (m, 1 H), 7.14–7.07 (m, 1 H), 6.28 (d, J = 8.3 Hz, 1 H), 3.85–
3.70 (m, 1 H), 3.64 (s, 3 H), 3.29 (s, 2 H), 2.06–1.95 (m, 2 H), 1.84–1.72
(m, 2 H), 1.65 (dd, J = 9.1, 3.4 Hz, 1 H), 1.52–1.17 (m, 5 H).
1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 8.0 Hz, 1 H), 7.61 (d, J = 8.2
Hz, 1 H), 7.53 (dd, J = 11.4, 3.9 Hz, 1 H), 7.13 (dd, J = 11.0, 4.0 Hz, 1 H),
7.03 (q, J = 8.0 Hz, 4 H), 5.81 (t, J = 5.8 Hz, 1 H), 3.41 (dd, J = 13.5, 6.7
Hz, 2 H), 2.27 (s, 3 H), 1.61–1.51 (m, 2 H), 1.33–1.24 (m, 4 H), 0.87 (t,
J = 6.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 160.5, 159.5, 142.3, 135.6, 135.4,
132.4, 130.0, 129.9 (2 C), 125.4 (2 C), 123.1, 121.9, 114.8, 75.9, 41.9,
29.9, 28.8, 22.3, 20.9, 13.9.
HRMS (ESI): m/z [M•]+ calcd for C21H23NO2S: 353.1449; found:
353.1448.
13C NMR (75 MHz, CDCl3): δ = 171.3, 160.7, 159.3, 142.4, 135.5, 130.3,
122.9, 121.5, 114.9, 52.7, 50.8, 36.8, 33.8, 25.6, 24.9.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–L

K
S. Ponra et al.
Paper
Synthesis
3-[(2,6-Dimethylphenyl)amino]-4-(p-tolylthio)-1H-isochromen-
3-(2,6-Dimethylphenylamino)-4-(dodecylthio)-1H-isochromen-1-
1-one (3bf)
one (3mf)
Starting from 2-carboxybenzaldehyde (4a) (165 mg, 1.1 mmol), 4-
methylbenzenethiol (5b) (124 mg, 1.0 mmol), 2,6-dimethylphenyliso-
cyanide (2f) (197 mg, 1.5 mmol), TiCl4 (1.2 mL, 1 M in CH2Cl2, 1.2
mmol) and following the general procedure C, then purification of the
crude material by flash column chromatography on silica gel using
cyclohexane/ethyl acetate (8:2) as eluent gave 3bf as a yellow solid
(190 mg, 49% yield); mp 135–141 °C.
Starting from 2-carboxybenzaldehyde (4a) (165 mg, 1.1 mmol), do-
decane-1-thiol (5m) (240 μL, 1.0 mmol), 2,6-dimethylphenylisocya-
nide (2f) (197 mg, 1.5 mmol), TiCl4 (1.2 mL, 1 M in CH2Cl2, 1.2 mmol)
and following the general procedure C, then purification of the crude
material by flash column chromatography on silica gel using cyclo-
hexane/ethyl acetate (99:1) as eluent gave 3mf as a pasty orange solid
(236 mg, 51% yield).
1H NMR (300 MHz, CDCl3): δ = 8.13 (dd, J = 8.0, 1.4 Hz, 1 H), 7.78–7.72
(m, 1 H), 7.65–7.55 (m, 1 H), 7.24–7.15 (m, 2 H), 7.13–7.06 (m, 7 H),
2.30 (s, 3 H), 2.20 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 160.1, 158.0, 141.9, 136.1, 135.69,
135.65, 133.6, 133.1, 132.0, 130.3, 130.1, 128.5, 128.2, 127.5, 125.7,
123.7, 122.2, 115.6, 20.9, 18.4.
1H NMR (300 MHz, CDCl3): δ = 8.17–8.06 (m, 1 H), 7.91 (d, J = 8.2 Hz, 1
H), 7.67 (s, 1 H), 7.34 (s, 1 H), 7.22–7.13 (m, 4 H), 2.77–2.67 (m, 2 H),
2.33 (s, 6 H), 1.77–1.65 (m, 2 H), 1.51–1.23 (m, 18 H), 0.93 (t, J = 6.6
Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 160.1, 157.4, 142.2, 136.1, 135.3, 134.2,
130.1, 128.5, 127.3, 123.3, 122.2, 115.8, 79.9, 34.8, 32.0, 30.1, 29.7 (3
C), 29.5, 29.4, 29.3, 29.1, 22.7, 18.6, 14.2.
HRMS (ESI): m/z [M•]+ calcd for C24H21NO2S: 387.1293; found:
387.1286.
HRMS (ESI): m/z [M•]+ calcd for C29H39NO2S: 465.2702; found:
465.2710.
4-(Dodecylthio)-3-(pentylamino)-1H-isochromen-1-one (3mc)
3-(Cyclohexylamino)-7-methyl-4-(p-tolylthio)-1H-isochromen-1-
one (3b′b)
Starting from 2-carboxybenzaldehyde (4a) (165 mg, 1.1 mmol), do-
decane-1-thiol (5m) (240 μL, 1.0 mmol), pentylisocyanide (2c) (189
μL, 1.5 mmol), TiCl4 (1.2 mL, 1 M in CH2Cl2, 1.2 mmol) and following
the general procedure C, then purification of the crude material by
flash column chromatography on silica gel using cyclohexane/ethyl
acetate (99:1) as eluent gave 3mc as a yellow sticky gum (163 mg,
38% yield).
1H NMR (300 MHz, CDCl3): δ = 8.11–8.01 (m, 1 H), 7.75 (d, J = 7.9 Hz, 1
H), 7.60–7.50 (m, 1 H), 7.12–7.05 (m, 1 H), 5.90 (t, J = 6.0 Hz, 1 H), 3.40
(dd, J = 13.3, 6.9 Hz, 2 H), 2.55–2.47 (m, 2 H), 1.65–1.40 (m, 4 H), 1.40–
1.17 (m, 22 H), 0.95–0.80 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 160.7, 159.1, 142.7, 135.2, 130.0, 122.7,
122.0, 115.0, 78.8, 41.9, 34.7, 32.0, 30.1, 29.8, 29.7 (3 C), 29.6, 29.4,
29.3, 29.0 (2 C), 22.7, 22.4, 14.1, 14.0.
HRMS (ESI): m/z [M•]+ calcd for C26H41NO2S: 431.2858; found:
431.2849.
Starting from 2-formyl-5-methylbenzoic acid (4b) (100 mg, 0.61
mmol), 4-methylbenzenethiol (5b) (69.0 mg, 0.55 mmol), cyclohex-
ylisocyanide (2b) (103 μL, 0.83 mmol), TiCl4 (665 μL, 1 M in CH2Cl2,
0.665 mmol) and following the general procedure C, then purification
of the crude material by flash column chromatography on silica gel
using cyclohexane/ethyl acetate (99:1) as eluent gave 3b′b as a yellow
crystalline solid (109.1 mg, 52% yield); mp 138–140 °C.
1H NMR (300 MHz, CDCl3): δ = 7.93 (s, 1 H), 7.51 (d, J = 8.3 Hz, 1 H),
7.34 (dd, J = 8.3, 1.6 Hz, 1 H), 7.07–6.97 (m, 4 H), 5.63 (d, J = 8.5 Hz, 1
H), 3.87–3.72 (m, 1 H), 2.31 (d, J = 23.5 Hz, 6 H), 1.97 (dd, J = 12.3, 3.0
Hz, 2 H), 1.77–1.55 (m, 3 H), 1.48–1.12 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 160.9, 158.7, 140.0, 137.1, 135.4, 133.0,
132.7, 130.0, 129.5, 125.7, 122.2, 115.0, 76.5, 50.8, 33.9, 25.5, 24.8,
21.0, 20.9.
HRMS (ESI): m/z [M•]+ calcd for C23H25NO2S: 379.1606; found:
379.1595.
3-(Benzylamino)-4-(dodecylthio)-1H-isochromen-1-one (3md)
Starting from 2-carboxybenzaldehyde (4a) (165 mg, 1.1 mmol), 1-do-
decanethiol (5m) (241 μL, 1.0 mmol), benzylisocyanide (2d) (183 μL,
1.5 mmol), TiCl4 (1.2 mL, 1 M in CH2Cl2, 1.2 mmol) and following the
general procedure C, then purification of the crude material by flash
column chromatography on silica gel using cyclohexane/ethyl acetate
(9:1) as eluent gave 3md as a yellow pasty residue (277 mg, 61%
yield).
1H NMR (300 MHz, CDCl3): δ = 8.11 (dd, J = 8.0, 0.9 Hz, 1 H), 7.81–7.76
(m, 1 H), 7.65–7.55 (m, 1 H), 7.38–7.33 (m, 4 H), 7.34–7.28 (m, 1 H),
7.20–7.10 (m, 1 H), 6.18 (t, J = 6.2 Hz, 1 H), 4.61 (d, J = 6.2 Hz, 2 H),
2.51 (t, J = 7.4 Hz, 2 H), 1.55–1.42 (m, 2 H), 1.24 (d, J = 8.4 Hz, 18 H),
0.88 (t, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 160.5, 158.4, 142.4, 138.2, 135.3, 130.0,
128.8 (2 C), 127.7, 127.6 (2 C), 123.1, 122.1, 115.3, 79.8, 45.9, 34.7,
31.9, 29.7, 29.6 (2 C), 29.6, 29.5, 29.3, 29.2, 29.0, 22.7, 14.1.
HRMS (ESI): m/z [M•]+ calcd for C28H37NO2S: 451.2545; found:
451.2544.
3-(Cyclohexylamino)-7-methoxy-4-(p-tolylthio)-1H-isochromen-
1-one (3b′′b)
Starting from 2-formyl-5-methoxybenzoic acid (4c) (100 mg, 0.55
mmol), 4-methylbenzenethiol (5b) (63.0 mg, 0.50 mmol), cyclohex-
ylisocyanide (2b) (94 μL, 0.75 mmol), TiCl4 (600 μL, 1 M in CH2Cl2, 0.6
mmol) and following the general procedure C, then purification of the
crude material by flash column chromatography on silica gel using
cyclohexane/ethyl acetate (99:1) as eluent gave 3b′′b as a yellow solid
(112.3 mg, 57% yield); mp 118–120 °C.
1H NMR (300 MHz, CDCl3): δ = 7.61–7.45 (m, 2 H), 7.15 (dd, J = 8.9, 2.8
Hz, 1 H), 7.08–6.95 (m, 4 H), 5.57 (d, J = 8.6 Hz, 1 H), 3.87–3.71 (m, 4
H), 2.26 (s, 3 H), 2.04–1.91 (m, 2 H), 1.75–1.55 (m, 3 H), 1.48–1.09 (m,
5 H).
13C NMR (75 MHz, CDCl3): δ = 160.7, 158.1, 156.1, 136.4, 135.4, 132.6,
129.9, 125.9, 125.6, 123.9, 115.5, 109.8, 76.6, 55.7, 50.8, 33.9, 25.5,
24.7, 20.9.
HRMS (ESI): m/z [M•]+ calcd for C23H25NO3S: 395.1555; found:
395.1557.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–L

L
S. Ponra et al.
Paper
Synthesis
Funding Information
J. Org. Chem. 2012, 77, 1579. (i) Chinnagolla, R. K.; Jeganmohan,
M. Chem. Commun. 2012, 48, 2030. (j) Guo, X. X. J. Org. Chem.
2013, 78, 1660. (k) Frasco, D. A.; Lilly, C. P.; Boyle, P. D.; Ison, E.
A. ACS Catal. 2013, 3, 2421. (l) Unoh, Y.; Hirano, K.; Satoh, T.;
Miura, M. Tetrahedron 2013, 69, 4454. (m) Wang, H.; Han, X.; Lu,
X. Tetrahedron 2013, 69, 8626. (n) Li, X. G.; Liu, K.; Zou, G.; Liu, P.
N. Adv. Synth. Catal. 2014, 356, 1496. (o) Mo, J.; Wang, L.; Cui, X.
Org. Lett. 2015, 17, 4960. (p) Warratz, S.; Kornhaaß, C.;
Cajaraville, A.; Niepötter, B.; Stalke, D.; Ackermann, L. Angew.
Chem. Int. Ed. 2015, 54, 5513. (q) Prakash, R.; Shekarrao, K.;
Gogoi, S.; Boruah, R. C. Chem. Commun. 2015, 51, 9972.
(r) Zhang, J.; Han, X.; Lu, X. J. Org. Chem. 2016, 81, 3423. (s) Liu,
H.; Yang, Y.; Wu, J.; Wang, X.-N.; Chang, J. Chem. Commun. 2016,
52, 6801. (t) Zheng, M.; Huang, L.; Tong, Q.; Wu, W.; Jiang, H.
Eur. J. Org. Chem. 2016, 663.
This work has been supported by IDEX, referenced as «ANR-10-IDEX-
0001-02 PSL.
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Acknowledgment
A.N. thanks the Ecole Polytechnique for a fellowship and the authors
thank PSL, Chimie ParisTech, ENS and ENSTA-ParisTech for financial
support.
Supporting Information
Supporting information for this article is available online at
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Carpita, A.; Bellina, F.; Stabile, P.; Mannina, L. Tetrahedron 2003,
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Hong, J.; Weng, L.; Zhou, X. Tetrahedron 2012, 68, 1552. (g) Faizi,
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–L