Metal-free visible-light-promoted thiocyanation/cyclization cascade for the synthesis of thiocyanato-containing isoquinolinediones

Article abstract of DOI:10.1016/j.tet.2019.04.053

A visible-light induced metal-free thiocyanate radical addition/intramolecular cyclization cascade reaction for the synthesis of thiocyanato-containing isoquinolinediones from N-alkyl-N-methacryloylbenzamides is described. The organic dye 9-mesityl-10-methylacridinium perchlorate (Acr⁺-Mes ClO₄ ^?)is used as a photocatalyst, and cheap and readily available ammonium thiocyanate is used to provide thiocyanate radical by single-electron transfer pathway. The reaction completes the synthesis of C[sbnd]S and C[sbnd]C bonds in one pot with abundant molecular oxygen as the sole sacrificial reagent. The method is easy to implement, and 25 new compounds have been prepared in moderate to good yields under mild conditions. This is the first time that a thiocyanate group has been introduced into isoquinoline-1,3(2H,4H)-diones to construct highly functional drug-like molecules.

Full text of DOI:10.1016/j.tet.2019.04.053

Accepted Manuscript
Metal-free visible-light-promoted thiocyanation/cyclization cascade for the synthesis of
thiocyanato-containing isoquinolinediones
Yu-Jue Chen, Yan-Hong He, Zhi Guan
PII:
S0040-4020(19)30465-X
https://doi.org/10.1016/j.tet.2019.04.053
TET 30298
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 January 2019
Revised Date: 19 April 2019
Accepted Date: 23 April 2019
Please cite this article as: Chen Y-J, He Y-H, Guan Z, Metal-free visible-light-promoted thiocyanation/
cyclization cascade for the synthesis of thiocyanato-containing isoquinolinediones, Tetrahedron (2019),
doi: https://doi.org/10.1016/j.tet.2019.04.053.
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ACCEPTED MANUSCRIPT
visible light
NCS
R
N
-
O
Acr+-Mes ClO4
R1
R1
NH4SCN
+
N
AcOH, DCM, air
R
O
O
O
—
—
—
transition-metal free
O as only sacrificial reagent
2
25 new compounds, up to 89% yield

ACCEPTED MANUSCRIPT
Metal-free visible-light-promoted
thiocyanation/cyclization cascade for the synthesis of
thiocyanato-containing isoquinolinediones
Yu-Jue Chen, Yan-Hong He* and Zhi Guan*
Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering,
Southwest University, Chongqing 400715, China
E-mails: guanzhi@swu.edu.cn (for Z. Guan); heyh@swu.edu.cn (for Y.-H. He)
Abstract: A visible-light induced metal-free thiocyanate radical addition/intramolecular
cyclization cascade reaction for the synthesis of thiocyanato-containing isoquinolinediones from
N-alkyl-N-methacryloylbenzamides is described. The organic dye 9-mesityl-10-methylacridinium
-
perchlorate (Acr+-Mes ClO4 ) is used as a photocatalyst, and cheap and readily available
ammonium thiocyanate is used to provide thiocyanate radical by single-electron transfer pathway.
The reaction completes the synthesis of C-S and C-C bonds in one pot with abundant molecular
oxygen as the sole sacrificial reagent. The method is easy to implement, and 25 new compounds
have been prepared in moderate to good yields under mild conditions. This is the first time that a
thiocyanate group has been introduced into isoquinoline-1,3(2H,4H)-diones to construct highly
functional drug-like molecules.
Key words: photocatalysis; organic dye; thiocyanation; isoquinolinedione
1. Introduction
Thiocyanato-containing compounds are important building blocks in synthetic chemistry.1
For instance, they are vital precursors for the synthesis of organic sulfides such as thiols,2
disulfides,3 phosphonothioates,4 heterocycles,5 as well as tri- and difluoromethyl thioethers.6
Furthermore, isothiocyanates7 can be easily obtained from thiocyanates by simple molecular
1

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rearrangement. Additionally, thiocyanate can act as a safe cyanide reagent to avoid the toxic
cyanide source8 and be regarded as a pseudohalide acting as a leaving group.9 In order to
obtain organic thiocyanates, the strategies of oxidizing thiocyanate anion using various
oxidants such as halogen derivatives,10 CAN,11 oxone12 and azocompounds13 have been well
developed. Recently, photocatalysis strategy for the formation of thiocyanate radical from
thiocyanate salts have been reported,14 and this convenient method deserves further
development.
As
a
valuable moiety of agromedical and pharmaceutical chemistry,15
isoquinoline-1,3(2H,4H)-dione is found in plentiful biologically active substances such as
inhibitor of HIV-1 integrase,15a,15f HBV RNaseH inhibitor,15b selective inhibitors of the
CDK4,15h,15i inhibitors of IGF-1R15d etc. It has drawn increasing attention of medicinal and
synthetic chemists. In recent years, a general concise strategy for the direct construction of
isoquinoline-1,3(2H,4H)-dione derivatives from N-alkyl-N-methacryloylbenzamide by free
radical addition/cyclization cascade process has attracted great interest (Scheme 1).16 In order
to achieve this conversion, many efforts have been made to obtain various free radicals from
their respective precursors for the addition reaction with the olefin to initiate the cascade
reaction. The methods used can be divided into two categories. One of them uses
16f,16a
conventional oxidants such as PhI(OAc)2,16o AgNO3/Na2S2O8
and CuCl/DTBP16c etc.
Although these methods are effective, they have some disadvantages such as the use of
stoichiometric toxic oxidants and high temperatures making them difficult to handle and
control. The other uses photocatalytic method employing Ru(II) or Ir(III) complex as a metal
photosensitizer.16e,16i To date, a number of functional groups (including trifluoromethyl,16i
arylsulfonyl,16k and alkyl,16f etc.) have been introduced into the isoquinoline skeleton by this
radical addition/cyclization cascade strategy using conventional oxidation or photocatalytic
methods (Scheme 1, a), while the SCN group has not yet been touched.
Light is an inexhaustible, environmentally friendly and inexpensive source.17 Photocatalysis
has made great progress in the past few decades,18 and now, due to its mild conditions and
high efficiency, it has become the preferred synthetic method for many organic chemists to
design and construct new substances. In light of the previous research, we deem that it would
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be intriguing to combine the versatile synthetic unit thiocyanate with the valuable
isoquinoline-1,3(2H,4H)-dione. Herein we report a metal-free photocatalytic radical
thiocyanation/cyclization tandem reaction for the synthesis of thiocyanateo-containing
isoquinoline-1,3(2H,4H)-diones. The organic dye 9-mesityl-10-methylacridinium perchlorate
(Acr+-Mes ClO4 ) is used as a photocatalyst, which has been widely used in photocatalytic
-
reactions and usually leads to excellent results in recent years.19 In this reaction, molecular
oxygen of the air is the only sacrificial reagent. Incorporating the thiocyanate group into
isoquinoline-1,3(2H,4H)-dione structural motif to construct several highly functionalized
drug-like molecules which are never reported before would provide more valuable research
for current isoquinoline chemistry and fertilize the synthetic methods for C–S bond formation.
Scheme 1. Synthesis of isoquinoline-1,3-dione derivatives via radical addition/cyclization cascade
2. Results and discussion
In our initial study, we used NH4SCN as the source of thiocyanate radical, and selected the
reaction of NH4SCN with N-methacryloyl-N-methylbenzamide (1a) as a model reaction.
When the reaction was carried out in MeCN under an air atmosphere in the presence of rose
Bengal (2 mol%) with irradiation of a 23 W compact fluorescent lamp (CFL) at 35 oC for 48 h,
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the desired product 2a was isolated in 26% yield (see The Supporting Information (SI), Table
S1, entry 1). Encouraged by this result, we optimized a range of parameters to improve the
reaction (SI, Table S1-Table S4). Pleasantly, 2a could be obtained in 83% yield (Table 1,
entry 1) under the optimal conditions which consist of 1a (0.2 mmol, 1 equiv.), NH4SCN (0.6
mmol, 3 equiv.), AcOH (0.5 equiv.), Acr+-Mes ClO4 (2 mol%), dichloromethane (DCM, 1
-
o
mL), an air atmosphere and 35 C (SI, Table S4, entry 2). Increasing or decreasing the
reaction temperature resulted in lower yields (Table 1, entries 2 and 3). Compared to
NH4SCN, KSCN exhibited lower reactivity in this reaction (Table 1, entry 4). When the
reaction was carried out under argon instead of air, only a 17% yield was obtained (Table 1,
entry 5), indicating that air (O2) is essential in the reaction (compared to the 83% yield
obtained under air conditions). In addition, control experiments showed that light and
photocatalyst are indispensable for this reaction (Table 1, entries 6 and 7).
Table 1. Selected optimization experiments a
Entry
Variation from standard conditions
-
Yield (2a) %b
1
2
3
4
5
6
7
83
25 oC instead of 35 oC
40 oC instead of 35 oC
KSCN instead of NH4SCN
under argon instead of air
without light
52
66
54
17
no reaction
trace
without photocatalyst
a Unless otherwise noted, reaction conditions: A mixture of 1a (0.2 mmol), NH4SCN (0.6 mmol), AcOH (0.1
-
mmol), and Acr+-Mes ClO4 (2 mol%) in DCM (1.0 mL) was irradiated by a 23 W CFL in an air atmosphere at 35
oC for 36 h.
b Isolated yield.
Employing the optimized conditions, we investigated the substrate scope of this tandem
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reaction and the results are listed in Scheme 2. A series of methacryloyl benzamides 1
containing a variety of substituents on the benzene ring or N atom could react smoothly with
NH4SCN under the standard conditions to afford the desired products in moderate to good
yields.In general, it was found that the para-substituted methacryloyl benzamides exhibited
good compatibility regardless of the electronic nature of the substituents (such as methyl,
tert-butyl, methoxyl and halogen) (Scheme 2, 2b and 2e-i). The meta-methyl 1c could afford
2c in a good yield of 85%, while the ortho-methyl 1d gave a lower yield of 59% (2d)
probably due to steric effect. The meta-chloro 1j and meta-bromo 1k gave products 2j and 2k
in yields of 45% and 30%, respectively, and strong electron-withdrawing group -CF3
substituted methacryloyl benzamide can also afford 2l in 49% yield. Moreover, the
N-substituents also had a significant effect on the reactivity of methacryloyl benzamides 1.
Except for methyl group, groups such as ethyl, n-propyl, isopropyl, cyclopropyl and benzyl
on the N atom displayed good compatibility with the reaction (Scheme 2, 2m-q), whereas the
N-phenyl 1u had poor reactivity (Scheme 2, 2u). Investigations demonstrated that dimethyl,
dimethoxy and dichloro substituted methacryloyl benzamides (Scheme 2, 1r-t) also
performed well in the reaction, giving the corresponding products in moderate to satisfactory
yields (Scheme 2, 2r-t). Additionally, in order to further confirm the structure of the products,
we obtained the crystal structure of 2i (Figure 1).
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NCS
O
R
R
N
R1
NH4SCN, Acr+-Mes ClO4- (2 mol%)
R1
N
23 W CFL, AcOH (0.5 equiv.), DCM
O
N
O
O
2
1
NCS
NCS
NCS
NCS
O
O
O
O
N
N
N
O
O
O
O
2a
2b
2c
2d
59%
85%
89%
85%
NCS
NCS
NCS
NCS
O
F
O
O
O
Cl
O
N
N
N
O
N
O
O
O
2e
2f
2g
2h
89%
70%
71%
65%
NCS
NCS
NCS
NCS
O
O
Br
O
O
N
O
N
N
N
F3C
Cl
Br
O
O
O
2i 56%
NCS
2j 45%
2k 30%
NCS
2l 49
%
NCS
NCS
O
O
O
O
N
N
N
N
O
O
O
O
2m
2n
2o
2p
74%
67%
51%
42%
NCS
NCS
SCN
NCS
NCS
O
Cl
Cl
O
O
O
O
O
O
N
N
N
N
N
Bn
Ph
O
O
O
O
O
2u trace
2q
2r
2s
2t
46%
71%
62%
71%
Scheme 2. Substrate scope a
-
a Reaction conditions: 1 (0.2 mmol), NH4SCN (0.6 mmol), AcOH (0.1 mmol), and Acr+-Mes ClO4 (2 mol%) in
DCM (1.0 mL) was irradiated by a 23 W CFL in an air atmosphere at 35 oC for 36-48 h; isolated yields.
6

ACCEPTED MANUSCRIPT
Figure 1. Single-crystal X-ray diffraction analysis of 2i
It is worth noting that when the meta-position of benzene ring was substituted by methoxyl
or fluoro (1v and 1w), the cyclization reaction yielded a mixture of two regioselective
products (para- and ortho- cyclized products) (Scheme 3, 2va, 2vb, 2wa and 2wb). This may
be due to the lone pair in the 2p orbital of the ether oxygen atom and the fluorine atom, which
makes the α-radical (phenyl radical intermediate, as shown in SI, Scheme S2) more stable.
On the other hand, the steric effect of methoxyl leads to a lower yield of ortho-cyclization
(2vb) than para-cyclization (2va). However, the steric hindrance of fluorine is not significant,
so the yields of the para- (2wa) and ortho-cyclized (2wb) products are not much different.
Interestingly, the reaction of methacryloyl o-methoxylbenzamide (1x) afforded only the
dearomatized spiro product (Scheme 3, 2x). This may be because the lone pair on the ether
oxygen atom can make the radical in the α-position more stable, so the intermediate formed
by the ipso-attack of the free radical 1-A on the benzene ring is more stable than the
intermediate formed by the ortho-attack (as shown in SI, Scheme S3). However, for the
o-methyl substituted substrate (1d), since the methyl group cannot stabilize the α-position
radical like the methoxy group, it is not easy to form the spiro compound, and only the
product 2d was obtained. A possible mechanism for the formation of 2x is proposed (SI,
Scheme S3).
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Scheme 3. Regioselectivity studies and dearomatization
The synthetic potential of this photoreaction can be demonstrated by its scalability. A
gram-scale reaction of 1.22 g 1a was carried out with irradiation of two 23 W CFLs under the
standard conditions, providing the corresponding product 2a in 68% yield (Scheme 4, a).
Additionally, we explored the synthetic applications of the obtained thiocyanates. The SCN
group of the product 2a could be successfully converted to SCF2H6a and SCF320 with yields of
57% and 48%, respectively (Scheme 4, b).
8

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Scheme 4. Gram-scale experiment and synthetic applications
In order to understand the reaction mechanism, a series of control experiments were carried
out.
In
the
presence
of
commonly
used
radical
scavengers
2,2,6,6-tetra-methylpiperidine-N-oxyl (TEMPO) and 2,6-di-tert-butyl-4-methylphenol (BHT),
the reaction yields reduced to 12% and 22%, respectively (SI, Scheme S1), suggesting that
the reaction may proceed via a free radical pathway. To verify whether NH4SCN was
-
oxidized by the excited Acr+-Mes ClO4 , the fluorescence quenching experiments
-
(Stern-Volmer studies) of Acr+-Mes ClO4 were performed. The results showed that NH4SCN
-
effectively quenched the excited Acr+-Mes ClO4 but 1a did not (Figure 2, for details, see SI,
Figure S1 and Figure S2). According to previous literature, NH4SCN can be oxidized by the
-
excited Acr+-Mes ClO4 efficiently (E SCN/ SCN
•
-
= +0.61 V vs. SCE and E[Acr
+
•
=
-Mes]*/ [Acr -Mes]
+2.08 V vs. SCE).14a,19j Indeed, our cyclic voltammetry (CV) studies of the two substrates
suggested that 1a is more difficult to oxidize than NH4SCN (see SI, Figure S3 and Figure
S4). Moreover, an on/off visible light irradiation experiment was performed to verify whether
9

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the free radical chain propagation process is involved. The results showed that once the light
was turned off, the yield of the reaction basically stopped increasing, so we think that there
may be no radical chain propagation during the reaction (SI, Figure S5).21
NH
1a
4SCN
3.0
2.8
2.6
2.4
2.2
2.0
1.8
1.6
1.4
1.2
1.0
20
30
40
50
60
70
80
90
100
110
Concentration (mM)
-
Figure 2. Stern–Volmer plots of fluorescence quenching of 5*10-4 M Acr+-Mes ClO4 (DCM:
EtOH 3:1) by 1a and NH4SCN
On the basis of our exploratory experiments and previous literature, a plausible mechanism
is proposed (Scheme 5). Under the irradiation of visible light, Acr+-Mes is excited to
Acr+-Mes*, which extracts an electron from the thiocyanate anion to generate thiocyanate
radical and simultaneously produces Acr•-Mes. Molecular oxygen oxidizes Acr•-Mes back to
Acr+-Mes to complete the photocatalysis cycle, while producing superoxide anion radical
•-
+
•
(O2 ) which takes a proton from NH4 to form hydroperoxyl radical (HO2 ). The addition of
thiocyanate radical to 1 forms a C-S bond to provide an alkyl radical intermediate 1-A.
Cyclization on the aromatic ring of intermediate 1-A gives the cyclic radical intermediate 1-B,
•
which can be oxidized and deprotonated by HO2 to give the product 2.
10

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Scheme 5. Proposed possible mechanism.
3. Conclusion
-
In summary, we have successfully developed a novel Acr+-Mes ClO4 catalyzed thiocyanate
radical addition/intramolecular cyclization cascade reaction to achieve thiocyanato-containing
isoquinolinediones in moderate to good yields under mild visible light photocatalytic
conditions. To the best of our knowledge, all products are reported for the first time. This
reaction uses a cheap and readily available ammonium thiocyanate to provide thiocyanate
radical by single-electron transfer pathway, and completes the synthesis of C-S and C-C
bonds in one pot with abundant molecular oxygen as the sole sacrificial reagent. Due to the
involvement of inorganic salt, this reaction makes inorganic chemistry more closely related to
organic chemistry. We believe that this convenient metal-free method for the direct
construction of thiocyanoisoquinoline compounds will enrich the study of isoquinoline
chemistry and provide valuable examples for the formation of C-S bonds.
Experimental section
11

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General experimental details
-
Acr+-Mes ClO4 was purchased from TCI industrial corporation Shanghai, China. The
anhydrous dichloromethane (99.5%, SafeDry, with molecular sieves, water ≤50 ppm (by K.F.,
SafeSeal) was purchased from Adamas Reagent, Ltd. Other solvents were dried by molecular
sieves. Unless otherwise noted, all reagents were purchased from commercial suppliers and
used without further purification. Reactions were monitored by thin-layer chromatography
(TLC) with Haiyang GF 254 silica gel plates (Qingdao Haiyang chemical industry Co Ltd,
Qingdao, China) using UV light and vanillic aldehyde as visualizing agents. Flash column
chromatography was performed using 300-400 mesh silica gel at increased pressure. 1H NMR
13
spectra and C NMR spectra were respectively recorded on 600 MHz and 150 MHz NMR
spectrometers. Chemical shifts (δ) were expressed in ppm with TMS as the internal standard,
and coupling constants (J) were reported in Hz. High-resolution mass spectra were obtained
by using ESI ionization sources (Varian 7.0 T FTICR-MS) and ESI-TOF. Melting points were
taken on a WPX-4 apparatus (Yice instrument equipment Co Ltd, Shanghai) and were
uncorrected. Single-crystal X-ray diffraction analysis was obtained on Agilent SuperNova E.
General procedure for the synthesis of products 2
A 10 mL round-bottomed glass flask was charged with 1 (0.20 mmol, 1.0 equiv.), NH4SCN
-
(0.60 mmol, 3.0 equiv.), Acr+-Mes ClO4 (2 mol%), AcOH (6 ꢀL, 0.5 equiv.) and DCM (1
mL). The mixture was stirred at 35 oC under irradiation of a 23 W CFL (Philips) in an air
atmosphere. After completion of the reaction (monitored by TLC), the DCM was removed
from the reaction mixture. The residue was diluted with EtOAc (20 mL) and washed with
saturated brine (10 mL). The organic layers were dried over anhydrous Na2SO4 and
evaporated in vacuo. The desired product 2 was obtained after purification by flash
chromatography on silica gel with petroleum ether/ethyl acetate (10:1 to 5:1) as the eluent.
2,4-dimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione (2a). White solid (43.2
o
1
mg, 83%); Melting range: 91.3-92.0 C; H NMR (600 MHz, CDCl3) δ 8.35-8.33 (m, 1H),
7.75-7.72 (m, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 3.88 (d, J = 13.4 Hz, 1H),
12

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13
3.53 (d, J = 13.4 Hz, 1H), 3.44 (s, 3H), 1.76 (s, 3H); C NMR (150 MHz, CDCl3) δ 174.0,
163.5, 139.2, 134.6, 129.6, 128.8, 125.4, 125.3, 110.4, 48.7, 43.9, 29.3, 27.5. HRMS (ESI)
m/z 283.0510 (M + Na+), Cal. C13H12N2O2SNa+, 283.0512.
2,4,6-trimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione (2b). White solid
o
1
(49.1 mg, 89%); Melting range: 143.8-144.9 C; H NMR (600 MHz, CDCl3) δ 8.20 (d, J =
8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 3.86 (d, J = 13.4 Hz, 1H), 3.51 (d, J = 13.3
Hz, 1H), 3.41 (s, 3H), 2.48 (s, 3H), 1.72 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 174.2, 163.6,
145.7, 139.2, 129.8, 129.6, 125.8, 122.9, 110.6, 48.6, 43.7, 29.3, 27.4, 30.0. HRMS (ESI) m/z
297.0665 (M + Na+), Cal. C14H14N2O2SNa+, 297.0668.
2,4,7-trimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione (2c). White solid
o
1
(46.5 mg, 85%). Melting range: 105.7-107.3 C; H NMR (600 MHz, CDCl3) δ 8.14 (s, 1H),
7.54 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 3.87 (d, J = 13.3 Hz, 1H), 3.51 (d, J = 13.3
Hz, 1H), 3.44 (s, 3H), 2.48 (s, 3H), 1.73 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 174.2, 163.7,
139.0, 136.3, 135.5, 129.7, 125.2, 110.6, 48.4, 43.9, 29.3, 27.5, 21.0. HRMS (ESI) m/z
297.0665 (M + Na+), Cal. C14H14N2O2SNa+, 297.0668.
2,4,8-trimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione (2d). White solid
o
1
(32.3 mg, 59%); Melting range: 144.4-145.2 C; H NMR (600 MHz, CDCl3) δ 7.55 (t, J =
7.7 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 3.87 (d, J = 13.3 Hz, 1H), 3.50
13
(d, J = 13.3 Hz, 1H), 3.40 (s, 3H), 2.82 (s, 3H), 1.73 (s, 3H); C NMR (150 MHz, CDCl3) δ
173.7, 164.1, 143.5, 140.5, 133.3, 132.8, 123.7, 123.4, 110.7, 48.7, 44.1, 29.8, 27.5, 23.9.
HRMS (ESI) m/z 297.0671 (M + Na+), Cal. C14H14N2O2SNa+, 297.0668.
6-(tert-butyl)-2,4-dimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione
(2e).
o
White solid (56.5 mg, 89%); Melting range: 118.1-118.9 C;1H NMR (600 MHz, CDCl3) δ
8.24 (d, J = 8.3 Hz, 1H), 7.58 (dd, J = 8.3, 1.7 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 3.86 (d, J =
13
13.4 Hz, 1H), 3.55 (d, J = 13.4 Hz, 1H), 3.41 (s, 3H), 1.74 (s, 3H), 1.38 (s, 9H). C NMR
13

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(150 MHz, CDCl3) δ 174.4, 163.5, 158.6, 138.8, 129.5, 126.3, 122.8, 121.8, 110.6, 49.0, 43.8,
35.5, 31.0, 29.5, 27.4. HRMS (ESI) m/z 339.1135 (M + Na+), Cal. C17H20N2O2SNa+,
339.1138.
6-methoxy-2,4-dimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione (2f). White
solid (41.0 mg, 70%). Melting range: 143.1-142.5 oC; 1H NMR (600 MHz, CDCl3) δ 8.27 (d,
J = 8.8 Hz, 1H), 7.06 (dd, J = 8.8, 2.3 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 3.93 (s, 3H), 3.86 (d,
13
J = 13.4 Hz, 1H), 3.48 (d, J = 13.4 Hz, 1H), 3.40 (s, 3H), 1.72 (s, 3H); C NMR (150 MHz,
CDCl3) δ 174.1, 164.6, 163.2, 141.4, 132.0, 118.2, 114.42, 110.8, 110.7, 55.8, 48.8, 43.8, 29.4,
27.3. HRMS (ESI) m/z 313.0614 (M + Na+), Cal. C14H14N2O3SNa+, 313.0617.
6-fluoro-2,4-dimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione (2g). White
solid (40.4 mg, 71%); Melting range: 128.4-129.8 oC; 1H NMR (600 MHz, CDCl3) δ 8.39 (dd,
J = 8.8, 5.8 Hz, 1H), 7.29-7.26 (m, 1H), 7.13 (dd, J = 9.0, 2.1 Hz, 1H), 3.86 (d, J = 13.6 Hz,
1H), 3.46-3.44 (m, 4H), 1.77 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 173.5, 166.6 (d, J = 257
Hz), 162.6, 142.2 (d, J = 8.4 Hz), 132.8 (d, J = 9.8 Hz), 121.9 (d, J = 2.6 Hz), 116.9, 116.8,
112.6, 112.4, 110.0, 48.9, 43.9, 29.0, 27.5; 19F NMR (565 MHz, CDCl3) δ -101.58 (s). HRMS
(ESI) m/z 301.0413 (M + Na+), Cal. C13H11FN2O2SNa+, 301.0417.
6-chloro-2,4-dimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione (2h). White
solid (38.5 mg, 65%). Melting range: 173.3-174.4 oC; 1H NMR (600 MHz, CDCl3) δ 8.29 (d,
J = 8.5 Hz, 1H), 7.55 (dd, J = 8.5, 1.8 Hz, 1H), 7.43 (d, J = 1.7 Hz, 1H), 3.86 (d, J = 13.6 Hz,
13
1H), 3.48 – 3.44 (m, 4H), 1.77 (s, 3H). C NMR (150 MHz, CDCl3) δ 173.4, 162.7, 141.3,
140.9, 131.2, 129.4, 125.7, 123.9, 110.0, 48.7, 43.8, 29.0, 27.6. HRMS (ESI) m/z 317.0126
(M + Na+), Cal. C13H11ClN2O2SNa+, 317.0122.
6-bromo-2,4-dimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione (2i). White
solid (37.0 mg, 56%). Melting range: 171.7-173.3 oC; 1H NMR (600 MHz, CDCl3) δ 8.21 (d,
J = 8.4 Hz, 1H), 7.72 (dd, J = 8.4, 1.7 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H), 3.87 (d, J = 13.6 Hz,
14

ACCEPTED MANUSCRIPT
13
1H), 3.48 – 3.44 (m, 4H), 1.77 (s, 3H). C NMR (150 MHz, CDCl3) δ 173.3, 162.9, 141.0,
132.4, 131.2, 129.9, 128.7, 124.3, 110.0, 48.7, 43.8, 29.0, 27.6. HRMS (ESI) m/z 360.9617
(M + Na+), Cal. C13H11BrN2O2SNa+, 360.9617.
7-chloro-2,4-dimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione (2j). White
solid (26.3 mg, 45%). Melting range: 135.9-136.3 oC; 1H NMR (600 MHz, CDCl3) δ 8.30 (d,
J = 2.3 Hz, 1H), 7.68 (dd, J = 8.4, 2.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 3.87 (d, J = 13.5 Hz,
13
1H), 3.48 – 3.41 (m, 4H), 1.73 (s, 3H); C NMR (150 MHz, CDCl3) δ 173.5, 162.5, 137.5,
135.4, 134.7, 129.4, 127.0, 110.2, 48.6, 43.7, 29.3, 27.7. HRMS (ESI) m/z 317.0123 (M +
Na+), Cal. C13H11ClN2O2SNa+, 317.0122.
7-bromo-2,4-dimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione (2k). White
solid (19.7 mg, 30%). Melting range: 152.1-152.8 oC; 1H NMR (600 MHz, CDCl3) δ 8.46 (d,
J = 2.0 Hz, 1H), 7.84-7.82 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 3.87 (d, J = 13.5 Hz, 1H),
13
3.45-3.42 (m, 4H), 1.72 (s, 3H). C NMR (150 MHz, CDCl3) δ 173.5, 162.4, 138.0, 137.5,
132.5, 127.1, 123.1, 110.2, 48.6, 43.5, 29.2, 27.7. HRMS (ESI) m/z 360.9617 (M + Na+), Cal.
C13H11BrN2O2SNa+, 360.9617.
2,4-dimethyl-4-(thiocyanatomethyl)-7-(trifluoromethyl)isoquinoline-1,3(2H,4H)-dione
(2l). White solid (31.9mg, 49%). Melting range: 95.8-97.7 oC; 1H NMR (600 MHz, CDCl3) δ
8.61 (s, 1H), 7.96 (dd, J = 8.2, 1.2 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 3.92 (d, J = 13.6 Hz, 1H),
3.51-3.45 (m, 4H), 1.77 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 173.2, 162.4, 142.8,
131.2-131.3 (q, J = 33.0 Hz), 130.9-130.8 (m), 126.9 (q, J = 3.8 Hz), 126.4, 126.2, 123.2 (q, J
19
= 271.5 Hz), 110.0, 49.0, 43.4, 29.3, 27.7; F NMR (565 MHz, CDCl3) δ -63.00 (s). HRMS
(ESI) m/z 351.0384 (M + Na+), Cal. C13H10Cl2N2O2SNa+, 351.0386.
2-ethyl-4-methyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione (2m). Colorless oil
o
(40.6 mg, 74%). Melting range: 63.1-63.9 C; 1H NMR (600 MHz, CDCl3) δ 8.33 (d, J = 7.9
Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 4.15 –
15

ACCEPTED MANUSCRIPT
4.04 (m, 2H), 3.86 (d, J = 13.4 Hz, 1H), 3.55 (d, J = 13.4 Hz, 1H), 1.73 (s, 3H), 1.26 (t, J =
13
7.1 Hz, 3H); C NMR (150 MHz, CDCl3) δ 173.6, 163.1, 139.2, 134.5, 129.7, 128.8, 125.5,
125.3, 110.6, 48.6, 43.8, 36.1, 29.3, 13.1. HRMS (ESI) m/z 297.0669 (M + Na+), Cal.
C14H14N2O2SNa+, 297.0668.
4-methyl-2-propyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione (2n). Colorless
1
oil (38.4 mg, 67%). H NMR (600 MHz, CDCl3) δ 8.32 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 7.6
Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 4.07 – 3.95 (m, 2H), 3.85 (d, J =
13
13.3 Hz, 1H), 3.56 (d, J = 13.3 Hz, 1H), 1.80 – 1.64 (m, 5H), 0.97 (t, J = 7.4 Hz, 3H); C
NMR (150 MHz, CDCl3) δ 173.9, 163.3, 139.2, 134.5, 129.7, 128.8, 125.5, 125.3, 110.6, 48.7,
43.7, 42.5, 29.5, 21.2, 11.3. HRMS (ESI) m/z 311.0827 (M + Na+), Cal. C15H16N2O2SNa+,
311.0825.
2-cyclopropyl-4-methyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione (2o). White
solid (29.0 mg, 51%). Melting range: 101.1-102.4 oC; 1H NMR (600 MHz, CDCl3) δ 8.30 (d,
J = 7.9 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H),
3.85 (d, J = 13.3 Hz, 1H), 3.54 (d, J = 13.3 Hz, 1H), 2.81-2.77 (m, 1H), 1.70 (s, 3H),
1.22-1.15 (m, 2H), 0.85-0.80 (m, 1H), 0.70-0.65 (m, 1H); 13C NMR (150 MHz, CDCl3) δ
175.1, 164.3, 139.1, 134.5, 129.6, 128.8, 125.9, 125.3, 110.7, 49.1, 43.3, 29.3, 24.8, 8.6, 8.2.
HRMS (ESI) m/z 309.0667 (M + Na+), Cal. C14H14N2O2SNa+, 309.0668.
2-isopropyl-4-methyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione
(2p).
1
Colorless oil (24.2 mg 42%). H NMR (600 MHz, CDCl3) δ 8.30 (d, J = 7.9 Hz, 1H),
7.71-7.68 (m, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 5.24-5.17 (m, 1H), 3.84
13
(d, J = 13.3 Hz, 1H), 3.53 (d, J = 13.3 Hz, 1H), 1.71 (s, 3H), 1.50 (t, J = 7.1 Hz, 6H); C
NMR (150 MHz, CDCl3) δ 174.2, 163.6, 139.1, 134.3, 129.7, 128.8, 126.0, 125.1, 110.8, 49.0,
46.2, 43.6, 29.4, 19.8, 19.4. HRMS (ESI) m/z 311.0827 (M + Na+), Cal. C15H16N2O2SNa+,
311.0825.
16

ACCEPTED MANUSCRIPT
2-benzyl-4-methyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione (2q). White solid
o
1
(55.2 mg, 71%). Melting range: 114.2-115.0 C; H NMR (600 MHz, CDCl3) δ 8.32 (dd, J =
7.9, 0.9 Hz, 1H), 7.72-7.70 (m, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.43-7.41 (m, 3H), 7.30 (t, J =
7.5 Hz, 2H), 7.25-7.23 (m, 1H), 5.25-5.20 (m, 2H), 3.83 (d, J = 13.4 Hz, 1H), 3.55 (d, J =
13.4 Hz, 1H), 1.70 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 174.0, 163.3, 139.2, 136.7, 134.7,
129.9, 128.9, 128.6 (d, J = 15.7 Hz), 127.6, 125.4, 110.6, 48.9, 44.1, 43.7, 29.4. HRMS (ESI)
m/z 359.0822 (M + Na+), Cal. C19H16N2O2SNa+, 359.0825.
2,4,5,7-tetramethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione (2r). White solid
o
1
(35.5 mg, 62%). Melting range: 112.8-114.4 C; H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H),
13
7.31 (s, 1H), 3.96 (m, 2H), 3.42 (s, 3H), 2.58 (s, 3H), 2.40 (s, 3H), 1.80 (s, 3H); C NMR
(150 MHz, CDCl3) δ 175.2, 164.0, 139.9, 138.7, 135.3, 133.4, 128.8, 126.3, 110.3, 49.9, 40.8,
27.7, 27.0, 22.3, 20.7. HRMS (ESI) m/z 311.0826 (M + Na+), Cal. C15H16N2O2SNa+,
311.0825.
6,7-dimethoxy-2,4-dimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione
(2s).
o
1
White solid (47.4 mg, 71%). Melting range: 160.6-161.5 C; H NMR (600 MHz, CDCl3) δ
7.72 (s, 1H), 6.77 (s, 1H), 4.00 (s, 3H), 3.97(s, 3H), 3.88 (d, J = 13.4 Hz, 1H), 3.50 (d, J =
13
13.4 Hz, 1H), 3.40 (s, 3H), 1.72 (s, 3H). C NMR (150 MHz, CDCl3) δ 174.4, 163.3, 154.7,
149.7, 133.1, 118.4, 111.0, 110.7, 107.1, 56.4, 56.3, 48.6, 43.9, 29.5, 27.4. HRMS (ESI) m/z
343.0720 (M + Na+), Cal. C15H16N2O4SNa+, 343.0723.
6,7-dichloro-2,4-dimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione
(2t).
o
1
White solid (30.0mg, 46%). Melting range: 173.2-174.5 C; H NMR (600 MHz, CDCl3) δ
13
8.39 (s, 1H), 7.51 (s, 1H), 3.85 (d, J = 13.6 Hz, 1H), 3.42 (m, 4H), 1.74 (s, 3H); C NMR
(150 MHz, CDCl3) δ 173.0, 161.8, 139.6, 138.6, 134.1, 131.3, 127.7, 125.2, 109.9, 48.6, 43.6,
29.1, 27.7. HRMS (ESI) m/z 350.9731 (M + Na+), Cal. C13H10Cl2N2O2SNa+, 350.9732.
7-methoxy-2,4-dimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione
(2va).
17

ACCEPTED MANUSCRIPT
1
Colorless oil (26.6 mg, 38%). H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 2.7 Hz, 1H),
7.31-7.25 (m, 2H), 3.91 (s, 3H), 3.83 (d, J = 13.3 Hz, 1H), 3.46 (d, J = 13.3 Hz, 1H), 3.42 (s,
13
3H), 1.71 (s, 3H). C NMR (151 MHz, CDCl3) δ 173.2, 162.6, 158.8, 130.2, 125.6, 125.6,
121.7, 111.0, 109.5, 54.7, 47.2, 43.2, 28.2, 26.6. HRMS (ESI) m/z 313.0620 (M + Na+), Cal.
C14H14N2O3SNa+, 313.0617.
5-methoxy-2,4-dimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione
(2vb).
o
1
White solid (17.8 mg, 32%). Melting range: 111.6-113.2 C; H NMR (600 MHz, CDCl3) δ
8.01 (d, J = 7.9 Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 4.36 (d, J = 13.3
13
Hz, 1H), 3.98 (s, 3H), 3.81 (d, J = 13.3 Hz, 1H), 3.41 (s, 3H), 1.77 (s, 3H). C NMR (150
MHz, CDCl3) δ 175.1, 163.6, 156.9, 129.9, 127.0, 126.24, 122.0, 116.5, 111.0, 55.8, 49.1,
39.9, 27.6, 26.1. HRMS (ESI) m/z 313.0619 (M + Na+), Cal. C14H14N2O3SNa+, 313.0617.
7-fluoro-2,4-dimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione (2wa). White
solid (18.0 mg, 25%). Melting range: 98.9-99.9 oC; 1H NMR (600 MHz, CDCl3) δ 8.21 (d, J =
7.8 Hz, 1H), 7.58 (dd, J = 8.0, 5.1 Hz, 1H), 7.42-7.37 (m, 1H), 3.87 (s, 2H), 3.43 (s, 3H), 1.82
(s, 3H); 13C NMR (150 MHz, CDCl3) δ 173.7, 162.6 (d, J = 3.3 Hz), 160.0 (d, J = 247.5 Hz),
130.6 (d, J = 9.3 Hz), 127.4 (d, J = 3.4 Hz), 126.0 (d, J = 12 Hz), 125.9 (d, J = 3 Hz), 121.8 (d,
J = 22.5 Hz) ,109.9, 48.0 (d, J = 3.8 Hz), 40.9 (d, J = 7.1 Hz), 27.7, 27.0 (d, J = 3.8 Hz); 19F
NMR (565 MHz, CDCl3) δ -110.81 (s). HRMS (ESI) m/z 301.0417 (M + Na+), Cal.
C13H11FN2O2SNa+, 301.0417.
5-fluoro-2,4-dimethyl-4-(thiocyanatomethyl)isoquinoline-1,3(2H,4H)-dione
(2wb).
Colorless oil (20.4 mg, 28%). 1H NMR (600 MHz, CDCl3) δ 8.00-7.99 (m, 1H), 7.42-7.42 (m,
2H), 3.85 (d, J = 13.5 Hz, 1H), 3.46 (d, J = 13.5 Hz, 1H), 3.43 (s, 3H), 1.74 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 173.8, 162.6 (d, J = 2.6 Hz), 162.6 (d, J = 249 Hz), 135.01 (d, J = 3.3
Hz), 127.7 (d, J = 7.5 Hz), 127.6 (d, J = 7.5 Hz) 122.2 (d, J = 22.5 Hz), 116.0 (d, J = 24.0 Hz),
19
110.2, 48.6, 44.0, 29.4, 27.7; F NMR (565 MHz, CDCl3) δ -111.71 (s). HRMS (ESI) m/z
301.0415 (M + Na+), Cal. C13H11FN2O2SNa+, 301.0417.
18

ACCEPTED MANUSCRIPT
6-methoxy-2,4-dimethyl-4-(thiocyanatomethyl)-2-azaspiro[4.5]deca-6,9-diene-1,3,8-trion
o
1
e (2x). White solid (22.3 mg, 37%). Melting range: 151.3-153.3 C; H NMR (600 MHz,
CDCl3) δ 7.55 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 3.87 (d, J
= 13.3 Hz, 1H), 3.50 (d, J = 13.3 Hz, 1H), 3.40 (s, 3H), 2.82 (s, 3H), 1.73 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 185.1, 178.3, 171.4, 167.7, 137.1, 133.2, 112.1, 106.2, 58.4, 56.6, 52.7,
38.0, 26.0, 22.5. HRMS (ESI) m/z 329.0561 (M + Na+), Cal. C14H14N2O3SNa+, 329.0566.
2,4-dimethyl-4-(((trifluoromethyl)thio)methyl)isoquinoline-1,3(2H,4H)-dione
(3a).
Colorless oil (34.5 mg, 57%); 1H NMR (600 MHz, CDCl3) δ 8.29 (d, J = 7.2 Hz, 1H), 7.68 (t,
J = 7.0 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 3.81 (d, J = 12.9 Hz, 1H),
13
3.46-3.41 (m, 4H), 1.74 (s, 3H); C NMR (150 MHz, CDCl3) δ 174.3, 163.7, 140.4, 134.3,
130.2 (q, J = 304.0 Hz) 129.3, 128.4, 125.2, 125.1, 47.7, 40.3, 29.1, 27.3; 19F NMR (565 MHz,
CDCl3) δ -41.03 (s). HRMS (ESI) m/z 326.0429 (M + Na+), Cal. C13H12F3NO2SNa+,
326.0433.
4-(((difluoromethyl)thio)methyl)-2,4-dimethylisoquinoline-1,3(2H,4H)-dione (4a). White
1
solid (27.6 mg, 48%). Melting range: 84.5-85.8 oC; H NMR (600 MHz, CDCl3) δ 8.29-8.28
(m, 1H), 7.69-7.66 (m, 1H), 7.51-7.49 (m, 1H), 7.41 (d, J = 7.8 Hz, 1H), 6.49 (t, J = 57.0 Hz,
1H), 3.68 (d, J = 13.5 Hz, 1H), 3.40 (s, 3H), 3.33 (d, J = 13.5 Hz, 1H), 1.72 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 175.0, 163.9, 141.0, 134.2, 129.2, 128.2, 125.4, 125.2, 120.0 (m, J =
19
273.0 Hz), 48.5, 38.7, 29.0, 27.3; F NMR (565 MHz, CDCl3) δ -91.80 (d, J = 35.1 Hz).
HRMS (ESI) m/z 308.0525 (M + Na+), Cal. C13H13F2NO2SNa+, 308.0527.
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China
(No 21672174), and the Basic and Frontier Research Project of Chongqing
(cstc2015jcyjBX0106).
References
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