Visible-light-mediated selective thiocyanation/ipso-cyclization/oxidation cascade for the synthesis of thiocyanato-containing azaspirotrienediones

Article abstract of DOI:10.1016/j.tet.2019.130763

A visible-light-mediated metal-free thiocyanate radical addition/ipso-cyclization/oxidation cascade reaction for the synthesis of thiocyanato-containing azaspirotrienediones from N-phenylpropynamides is described. Cheap and readily available ammonium thiocyanate was used as a precursor to the thiocyanate free radical, which undergoes a radical addition reaction with the alkyne, followed by selective ipso-cyclization and oxidation to afford the dearomatized products. No product of ortho-cyclization was detected. The reaction completes the synthesis of C–S, C–C, and C[dbnd]O bonds in one pot, with abundant and renewable air oxygen as the sole sacrificial reagent and oxygen source.

Full text of DOI:10.1016/j.tet.2019.130763

Journal Pre-proof
Visible-light-mediated selective thiocyanation/ipso-cyclization/oxidation cascade for
the synthesis of thiocyanato-containing azaspirotrienediones
Yuan Chen, Yu-Jue Chen, Zhi Guan, Yan-Hong He
PII:
S0040-4020(19)31156-1
https://doi.org/10.1016/j.tet.2019.130763
TET 130763
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 August 2019
Revised Date: 31 October 2019
Accepted Date: 1 November 2019
Please cite this article as: Chen Y, Chen Y-J, Guan Z, He Y-H, Visible-light-mediated selective
thiocyanation/ipso-cyclization/oxidation cascade for the synthesis of thiocyanato-containing
azaspirotrienediones, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130763.
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Graphical Abstract
A visible-light-mediated metal-free thiocyanate radical addition/ipso-cyclization/oxidation cascade
reaction for the synthesis of thiocyanato-containing azaspirotrienediones from
N-phenylpropynamides is described.

Visible-light-mediated selective
thiocyanation/ipso-cyclization/oxidation cascade for
the synthesis of thiocyanato-containing
azaspirotrienediones
Yuan Chen, Yu-Jue Chen, Zhi Guan* and Yan-Hong He*
Key Laboratory of Luminescent and Real-Time Analytical Chemistry, Ministry of Education, 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-mediated
metal-free
thiocyanate
radical
addition/ipso-cyclization/oxidation cascade reaction for the synthesis of thiocyanato-containing
azaspirotrienediones from N-phenylpropynamides is described. Cheap and readily available
ammonium thiocyanate was used as a precursor to the thiocyanate free radical, which undergoes a
radical addition reaction with the alkyne, followed by selective ipso-cyclization and oxidation to
afford the dearomatized products. No product of ortho-cyclization was detected. The reaction
completes the synthesis of C-S, C-C, and C=O bonds in one pot, with abundant and renewable air
oxygen as the sole sacrificial reagent and oxygen source.
Key words: photocatalysis; organic dye; thiocyanation; ipso-cyclization, dearomatization
1. Introduction
A spirocyclic compound is a compound in which two monocyclic rings share the same
quaternary carbon atom in one molecule, and the shared carbon atom is called a spiro carbon atom
[1]. Spirocyclic compounds are widely used in polymer binders/expanders and fireproofing
materials due to their stable rigid structure [2]. Chiral spirocyclic compounds play an important
role as good chiral ligands in asymmetric catalysis owing to their difficulty in racemization [3]. In
addition, when the spiro ring system contains two π systems that are approximately perpendicular
1

to each other, the interesting spiroconjugation phenomenon occurs [4]. This special
homoconjugation makes it an important direction for cutting-edge materials [5]. The
azaspirohexadienone moiety is one of the most important structures in the biological and
pharmaceutical fields [6]. It can be found in many drug molecules and natural products, such as
antimalarial molecule [7], antiobesity agent [8], alkaloid discorhabdin C from sponges [9],
alkaloid annosqualine from the stems of Annona squamosa, and molecule with anti-proliferative
properties against the human breast cancer cell line MCF-7 [6b] (Scheme 1). Moreover, some
azaspirohexadienone-containing molecules are important intermediates in organic synthesis and
have been extensively used to construct high-value macromolecular compounds [10].
Scheme 1. Drugs and natural products containing azaspirohexadienone moiety
The synthesis of spirohexadienones is mainly realized through de-aromatization of the
aromatic rings by ipso nucleophilic or electrophilic addition [11]. Recently, a number of synthetic
methods for spirodihexenones have been developed. However, in most cases, phenol, a phenol
derivative or an excess of t-butylhydroperoxide is required as a source of carbonyl oxygen, which
not only limits the scope of application but is also harmful to the environment. Therefore, it is
still necessary to develope more green and mild synthetic methods for the synthesis of
spirohexadienones.
Some organic thiocyanates have been found in natural products [12]. Moreover, thiocyanato
is a valuable group with many functions in organic synthesis, so it has attracted increasing
2

attention from chemists in recent decades [13]. For example, thiocyanates can be used as
precursors to other thio functional groups [14]. Since the nitrile moiety acts as a leaving group, the
sulfur atom of the thiocyanate has an electrophilic property. Thiocyanate has the opposite
reactivity because it can be nucleophilic at its sulfur or its nitrogen end, which can be readily used
to convert organic thiocyanates to isothiocyanates by simple molecular rearrangement. Due to the
specific polarization of the electron-rich nitrile moiety of thiocyanate, these compounds represent
attractive cycloaddition partners to produce heterocycles and are therefore useful as precursors for
heterocycles. Additionally, thiocyanates can also be used as a source of cyanides [15]. Therefore,
the introduction of versatile thiocyanate into the spirohexadienone framework to obtain highly
functionalized novel compounds is of great significance for the study of spiro compounds. In
2008 [11e], Li's group reported the electrophilic spirocyclization reaction catalyzed by
electrophilic fluorination reagents at 90 oC. The halogenated and thiocyanated
spirocyclohexenylenediones were synthesized by using CuX (X = I, Br, SCN) to provide
functional groups, wherein four thiocyanate products were obtained in moderate yields.
Visible light is a clean energy source that is inexpensive, easy to obtain, rich in source, green
and renewable. Photoredox catalysis has been effectively used to drive chemical conversion in
organic synthesis and to construct molecules that are difficult to prepare by other methods [16].
Recently, it has been reported that thiocyanate radicals can be produced from thiocyanates by
photocatalysis, which can be combined with unsaturated compounds including indoles and
imidazoles to form various organic thiocyanates [17]. Inspired by previous work, we decided to
introduce thiocyanate group into spirocyclic skeleton by photocatalysis. Herein, we report the
synthesis of thiocyanato-containing azaspirotrienediones by cascade thiocyanate radical
addition/ipso-cyclization/oxidation. To the best of our knowledge, this is the first photocatalytic
reaction of thiocyanate with an alkyne. The reaction was carried out under mild and metal-free
conditions using acridinium perchlorate as an organic photocatalyst. The oxygen atom of the
newly formed carbonyl comes from the air oxygen, so there is no need to pre-functionalize the
benzene ring or add additional oxygen source. The air oxygen is also the only sacrificial agent in
the reaction.
2. Results and discussion
3

In our initial study, ammonium thiocyanate (NH4SCN) was used as the source of thiocyanate
and its reaction with N-phenylpropynamide (1a) was chosen as the model reaction. The reaction
was carried out using rose Bengal (2 mol%) as a photocatalyst in acetonitrile (MeCN, 1 mL) under
irradiation of a 23 W compact fluorescent lamp (CFL) at 35 °C for 48 h. The desired product 2a
was obtained in 11% yield and by-product 3a was isolated in 10% yield (see The Supporting
Information (SI), Table S1, entry 1) while the substrates were not completely consumed. After
screening some commonly used photocatalysts (SI, Table S1), acridinium perchlorate was
selected as the photocatalyst for the reaction (SI, Table S1, entry 2). The results of solvent
screening showed that in 1,2-dichloroethane (DCE), 2a was isolated as a single product in 41%
yield, while by-product 3a was only observed in a trace amount (SI, Table S2, entry 1). Next, the
effects of additives, photocatalyst loading and the molar ratio of 1a and NH4SCN on the reaction were
investigated (SI, Tables S3-S5). Ultimately, the desired product 2a was cheeringly obtained in 85%
yield (Table 1, entry 1) under the optimal conditions consisting of the following: 1a (0.2 mmol, 1
-
equiv.), NH4SCN (0.6 mmol, 3 equiv.), AcOH (6 ꢀL, 0.5 equiv.), Acr+-Mes ClO4 (2 mol%), DCE
(1 mL), in air atmosphere at 35 oC under irradiation of a 23 W CFL (SI, Table S5, entry 4).
In order to confirm this photocatalyzed reaction, some control experiments were conducted
(Table 1). The experimental results showed that both light and photocatalyst are indispensable for
the reaction (Table 1, entries 2 and 3). When the reaction was carried out under argon instead of
air, only a trace amount of product 2a was observed (Table 1, entry 4), indicating that air (O2) is
necessary in the reaction. To verify whether the reaction undergoes a radical pathway, radical
scavengers 2,2,6,6-tetramethylpiperidinyl-1-oxide (TEMPO) and butylated hydroxytoluene (BHT)
were separately added to the reaction system. It was found that in the presence of these radical
scavengers, the reaction was completely inhibited (Table 1, entries 5 and 6), indicating that the
reaction may involve a radical process. It is noteworthy that this reaction only selectively
produced the ipso-cyclized product and no ortho-cyclized product was observed.
Table 1. Control experiments a
4

Entry
Variation from standard conditions
--
Yield of 2a (%) b
85
1
2
3
4
5
6
Without photocatalyst
Without light
Trace
Not detected
Under argon instead of air
With BHT (1.5 equiv.)
With TEMPO (1.5 equiv.)
Trace
Trace c
Not detected
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 DCE (1.0 mL) was irradiated by a 23 W CFL in air atmosphere at 35 oC
b
for 24 h. Isolated yield. c 4a was detected by high resolution mass spectrometry (HRMS) (for the structure of 4a,
see Scheme 5; for HRMS spectrum, See SI).
Employing the optimized conditions, we investigated the substrate scope of this tandem
reaction and the results are listed in Scheme 2. A series of N-arylpropynamides could react
smoothly with NH4SCN under the optimal conditions to give the corresponding spirocyclic
products in moderate to good yields. The effect of the substituents at the phenyl ring attached to
the alkynyl group on the reaction was first investigated. The substrates with electron-donating
groups (methyl, methoxy) or electron-withdrawing groups (trifluoromethyl, halogen) on the
benzene rings reacted smoothly to give the corresponding products in satisfactory yields (2b-2h),
wherein the p-methyl substituted 1b provided the product 2b in 95% yield. The electronic nature
of the substituents on the N-phenyl moiety has a significant effect on the yield of the reaction. The
substrates with electron-donating groups (3-methyl, 2-methyl and 2-methoxy) gave corresponding
products with decent yields (2i, 2j and 2l), and those with electron-withdrawing groups (2-phenyl,
3-chloro, 3-bromo and 2-chloro) gave lower yields (2k and 2m-2o). This reaction was also
applicable to N-naphthylpropynamide, which gave the corresponding product 2p in 50% yield.
When the methyl group on the N atom was replaced with other alkyl groups such as ethyl,
isopropyl and benzyl, these substrates were also compatible with the reaction, giving the
5

corresponding products in satisfactory yields (2q-2s). When the N atom was bonded to the
electron-withdrawing group acetyl, the reaction required a longer time to obtain 2t in 45% yield,
and the substrate 1t could not be completely consumed. Further, in addition to the aryl alkyne, an
alkyl alkyne was also suitable for the reaction, which gave the corresponding product 2u in 57%
yield. It is worth noting that this reaction could also be used to construct the tricyclic structure
(2v).
6

Scheme 2. Substrate scope a
a Unless otherwise noted, reaction conditions: A mixture of 1 (0.2 mmol), NH4SCN (0.6 mmol), AcOH (0.1 mmol),
-
o
and Acr+-Mes ClO4 (2 mol%) in DCE (1.0 mL) was irradiated by a 23 W CFL in an air atmosphere at 35 C for
15-36 h. Isolated yield. b 48 h.
Next, we investigated the reaction efficiency when the amide group of 1a was replaced with
the ester group (5a) under standard conditions. Interestingly, the reaction gave the ortho-cyclized
product 6a in 33% yield instead of the desired ipso-cyclized product. Even after 72 h of reaction,
there was still a large amount of starting material remaining (Scheme 3).
Scheme 3. The reaction using phenyl 3-phenylpropiolate (5a)
To further understand the reaction mechanism, a series of experiments were carried out. The
-
fluorescence quenching experiments (Stern-Volmer studies) of Acr+-Mes ClO4 were performed to
verify which substrate first reacts with the excited photocatalyst. The results showed that NH4SCN
-
effectively quenched the excited Acr+-Mes ClO4 but 1a did not show significant quenching
(Figure 1, for details, see SI, Figures S1 and S2). Next, the cyclic voltammetry experiments were
conducted, and the oxidation potentials of 1a and NH4SCN were determined as: 1a had no
apparent oxidation peak in the range of 0-2.4 V (SI, Figure S3) and NH4SCN had an obvious
oxidation peak (Eox = +0.729 V in MeCN) (SI, Figure S4). The data indicated that NH4SCN
-
instead of 1a can be oxidized by the excited Acr+-Mes ClO4 (E [Acr+-Mes]* /[Acr -Mes]
·
= +2.08 V vs.
SCE in MeCN).11a In addition, to verify whether a radical chain propagation process is involved,
an on/off visible light irradiation experiment was performed. The results showed that even if the
light was turned off, the yield of the reaction continued to increase slightly, so we speculate that
7

there may be radical chain propagation during the reaction (SI, Figure S5).
Figure 1. Stern–Volmer plots of fluorescence quenching of 5*10-4 M Acr+-Mes ClO4
-
We then explored the oxygen atom source of the newly formed carbonyl group. Since the
above reactions were carried out under ambient conditions, both water and oxygen can be a source
of oxygen. Thus, we investigated the effect of water and oxygen on the reaction (Scheme 4).
Firstly, under anhydrous and anaerobic conditions, the model reaction was completely inhibited.
Secondly, without oxygen, in the presence of 2 equivalents of water, the reaction also could not
proceed. Finally, under anhydrous conditions in the presence of oxygen (oxygen balloon), the
reaction proceeded smoothly to give the product 2a in 85% yield. The results of these experiments
indicated that oxygen participates in the reaction while water does not, so we speculated that the
oxygen atom of the newly formed carbonyl in 2a is derived from oxygen in the air. To further
confirm this speculation, we performed an 18O labeling experiment. The model reaction was
carried out under 18O2 conditions (18O2 balloon) to give the 18O-labeled product 7a (detected by
HRMS), which clearly demonstrated the reliability of our conclusion.
8

Scheme 4. Effect of water and oxygen on the reaction
Based on our control experiments and previous literatures [18], we proposed a possible
mechanism for the reaction (Scheme 5). Under visible light irradiation, Acr+-Mes is excited to
Acr+-Mes* and then undergoes single electron transfer (SET) with thiocyanate anion to produce
thiocyanate radical and Acr•-Mes. Acr•-Mes is oxidized back to Acr+-Mes by air oxygen to
•-
complete the photocatalytic cycle, and simultaneously the superoxide anion radical (O2 ) is
+
•
produced, which obtains a proton from NH4 to form the hydrogen peroxy radical (HO2 ). The
addition of thiocyanate radical to alkyne 1a forms a C-S bond to give the alkenyl radical
intermediate 2-A, which was captured by BHT (4a was detected by HRMS). 2-A undergoes
5-exo-trig ipso-cyclization to give the dearomatized intermediate 2-B1, and there is resonance
between 2-B1 and 2-B2. 2-B2 can undergoes three possible reaction pathways: (i) 2-B2 can be
coupled with the thiocyanate radical to give 3a which was isolated as a by-product during the
•
optimization of the reaction conditions. (ii) 2-B can be captured by hydroperoxy radical (HO2 ) to
form peroxide intermediate 2-D. (iii) 2-B can be captured by air oxygen to give the intermediate
2-C. 2-C undergoes a SET with the thiocyanate anion and then combines with a proton to form
9

2-D, which results in radical chain propagation. Finally, dehydration of 2-D gives the desired
product 2a.
Scheme 5. Proposed reaction mechanism
3. Conclusion
We have successfully developed
a
metal-free photocatalytic thiocyanate radical
addition/ipso-cyclization/oxidation cascade reaction for the synthesis of thiocyanato-containing
azaspirotrienediones from N-phenylpropynamides. The organic dye acridinium perchlorate was
used as a photocatalyst. Cheap and readily available ammonium thiocyanate was used as a
precursor to the thiocyanate free radical, which undergoes a radical addition reaction with the
alkyne, followed by selective ipso-cyclization to afford the dearomatized products. No product of
10

ortho-cyclization was detected. Twenty-two products were synthesized with yields of up to 95%,
of which eighteen are new compounds. The reaction completes the synthesis of C-S, C-C and
C=O bonds in one pot. Abundant and renewable air oxygen acts as the sole sacrificial reagent and
oxygen source, so there is no need to pre-functionalize the benzene ring or add additional oxygen
source. The reaction has the advantages of mild reaction conditions, simple operation, good
functional group compatibility and wide range of substrate scope.
4. Experimental section
4.1
General experimental details
Acr+-Mes ClO4 was purchased from TCI industrial corporation Shanghai, China. The
anhydrous 1,2-dichloroethane (DCE) (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
-
1
performed using 200-300 mesh silica gel at increased pressure. H NMR spectra and 13C 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 (HRMS) were obtained by using ESI ionization
sources (Varian 7.0 T FTICR-MS), ESI-TOF and Q-TOF. Melting points were taken on a WPX-4
apparatus (Yice instrument equipment Co Ltd, Shanghai) and were uncorrected.
4.2
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 DCE (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 DCE 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 residue was
11

purified by flash chromatography on silica gel with petroleum ether/ethyl acetate (10:1 to 2:1) as
the eluent to give the desired product 2.
4.2.1 1-Methyl-4-phenyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione[11e] (2a)
o
1
White solid (53.3 mg, 85%); Melting range: 157.8-158.6 C; H NMR (600 MHz, CDCl3) δ
7.48-7.41 (m, 3H), 7.27 (d, J = 7.6 Hz, 2H), 6.53 (s, 4H), 2.95 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 183.2, 164.9, 157.0, 143.1, 134.0, 131.1, 129.1, 128.9, 127.8, 122.4, 106.2, 68.4, 26.6.
IR (KBr) ν 3076, 2168, 1715, 1671, 1659, 1617, 1563, 1493, 1459, 1367, 1275, 873, 736, 690
cm-1. HRMS m/z 331.0515 (M + Na+), Cal. C17H12N2O2SNa+, 331.0512.
4.2.2 1-Methyl-3-thiocyanato-4-(p-tolyl)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (2b) White
solid (60.1 mg, 95%); Melting range: 140.5-141.9 oC; 1H NMR (600 MHz, CDCl3) δ 7.20 (d, J =
17.6 Hz, 4H), 6.53 (d, J = 1.4 Hz, 4H), 2.94 (s, 3H), 2.37 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
183.4, 165.1, 157.4, 143.3, 141.7, 133.8, 129.8, 127.7, 126.1, 121.5, 106.4, 68.3, 26.5, 21.4. IR
(KBr) ν 3126, 2178, 1713, 1673, 1640, 1605, 1583, 1497, 1457, 1397, 1358, 864, 755 cm-1.
HRMS m/z 345.0664 (M + Na+), Cal. C18H14N2O2SNa+, 345.0668.
4.2.3
4-(4-Methoxyphenyl)-1-methyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione
o
1
[11e] (2c) White solid (51.0 mg, 75%); Melting range: 154.9-155.7 C; H NMR (600 MHz,
CDCl3) δ 7.31 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 6.55 (d, J = 10.2 Hz, 2H), 6.52 (d, J
= 10.3 Hz, 2H), 3.83 (s, 3H), 2.93 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 183.4, 165.3, 161.8,
157.1, 143.6, 133.7, 129.5, 121.2, 120.3, 114.6, 106.6, 68.2, 55.4, 26.4. IR (KBr) ν 3145, 2168,
1722, 1678, 1635, 1605, 1575, 1506, 1457, 1398, 1363, 874, 825 cm-1. HRMS m/z 361.0620 (M
+ Na+), Cal. C18H14N2O3SNa+, 361.0617.
4.2.4
4-(3-Methoxyphenyl)-1-methyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione
o
1
(2d) White solid (51.3 mg, 76%); Melting range: 156.9-158.2 C; H NMR (600 MHz, CDCl3) δ
7.34 (t, J = 8.0 Hz, 1H), 6.99 (dd, J = 8.3, 2.0 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.78 (s, 1H), 6.54
(d, J = 10.6 Hz, 2H), 6.52 (d, J = 10.6 Hz, 2H), 3.78 (s, 3H), 2.95 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 183.3, 164.9, 159.8, 156.8, 143.1, 133.9, 130.3, 130.1, 122.4, 120.0, 116.3, 113.7, 106.2,
68.3, 55.4, 26.5. IR (KBr) ν 3136, 2168, 1710, 1654, 1643, 1609, 1586, 1506, 1467, 1358, 1298,
854, 795, 746, 706 cm-1. HRMS m/z 361.0620 (M + Na+), Cal. C18H14N2O3SNa+, 361.0617.
4.2.5
12

1-Methyl-3-thiocyanato-4-(4-(trifluoromethyl)phenyl)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione
o
1
(2e) White solid (69.9 mg, 85%); Melting range: 158.9-160.8 C; H NMR (600 MHz, CDCl3) δ
7.70 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 6.54 (s, 4H), 2.97 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 182.8, 164.5, 155.0,142.5, 134.3, 132.9 (q, J = 33.5 Hz), 132.4, 128.5, 126.1 (d, J = 3.7
Hz), 124.2, 122.4, 105.6, 68.4, 26.7. IR (KBr) ν 3116, 2168, 1733, 1635, 1601, 1567, 1500, 1442,
1342, 1319, 874, 844 cm-1. HRMS m/z 399.0381 (M + Na+), Cal. C18H11F3N2O2SNa+, 399.0386.
4.2.6 4-(4-Fluorophenyl)-1-methyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (2f)
1
White solid (53.9 mg, 78%); Melting range: 127.0-128.3 oC; H NMR (600 MHz, CDCl3) δ 7.30
(dd, J = 8.3, 5.2 Hz, 2H), 7.13 (t, J = 8.4 Hz, 2H), 6.54 (d, J = 10.4 Hz, 2H), 6.52 (d, J = 10.5 Hz,
2H), 2.95 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 183.1, 164.9, 164.0 (d, J = 252 Hz), 163.2,
155.7, 143.0, 134.1, 130.1 (d, J = 8.7 Hz), 124.9 (d, J = 3.5 Hz), 122.8, 116.6, 116.4, 106.0, 68.4,
26.6. IR (KBr) ν 3116, 2168, 1733, 1635, 1601, 1567, 1500, 1442, 1342, 1319, 874, 844 cm-1.
HRMS m/z 349.0420 (M + Na+), Cal. C17H11FN2O2SNa+, 349.0417.
4.2.7 4-(4-Chlorophenyl)-1-methyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (2g)
White solid (58.6 mg,76%); Melting range: 177.9-179.3 oC; 1H NMR (600 MHz, CDCl3) δ 7.41
(d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 6.54 (d, J = 9.9 Hz, 2H), 6.51 (d, J = 10.1 Hz, 2H),
2.95 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 183.0, 164.7, 155.5, 142.8, 137.5, 134.2, 129.5, 129.2,
127.2, 123.0, 105.9, 68.4, 26.6. IR (KBr) ν 3096, 2168, 1713, 1674, 1644, 1607, 1585, 1476, 1427,
1348, 1278, 835, 766 cm-1. HRMS m/z 365.0120 (M + Na+), Cal. C17H11ClN2O2SNa+, 365.0122.
4.2.8 4-(4-Bromophenyl)-1-methyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (2h)
1
White solid (43.1 mg, 55%); Melting range: 173.5-174.7 oC; H NMR (600 MHz, CDCl3) δ 7.57
(d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 6.54 (d, J = 10.1 Hz, 2H), 6.51 (d, J = 10.3 Hz, 2H),
2.95 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 183.0, 164.7, 155.6, 142.8, 134.2, 132.5, 129.3, 127.7,
125.8, 123.0, 105.9, 68.3, 26.6. IR (KBr) ν 3102, 2148, 1721, 1681, 1642, 1602, 1582, 1504, 1461,
1403, 1383, 846, 827 cm-1. HRMS m/z 408.9618 (M + Na+), Cal. C17H11BrN2O2SNa+, 408.9617.
4.2.9 1,7-Dimethyl-4-phenyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (2i) White
solid (50.5 mg, 77%); Melting range: 165.2-166.9 oC; 1H NMR (600 MHz, CDCl3) δ 7.48-7.42 (m,
3H), 7.27 (d, J = 6.7 Hz, 2H), 6.54 (d, J = 9.7 Hz, 1H), 6.49 (d, J = 9.6 Hz, 1H), 6.39 (s, 1H), 2.86
(s, 3H), 1.77 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 184.0, 165.4, 157.4, 151.5, 143.2, 133.5,
132.6, 131.3, 129.2, 128.8, 127.6, 122.5, 106.2, 70.6, 26.1, 17.6. IR (KBr) ν 3122, 2168, 1731,
1673, 1635, 1612, 1575, 1486, 1447, 1384, 1363, 896, 746, 696 cm-1. HRMS m/z 345.0666 (M +
Na+), Cal. C18H14N2O2SNa+, 345.0668.
13

4.2.10 1,6-Dimethyl-4-phenyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (2j)
o
1
White solid (49.2 mg, 75%); Melting range: 142.3-143.3 C; H NMR (600 MHz, CDCl3) δ
7.47-7.40 (m, 3H), 7.23 (d, J = 7.2 Hz, 2H), 6.49 (s, 2H), 6.30 (s, 1H), 2.93 (s, 3H), 1.95 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 184.1, 164.9, 157.8, 142.9, 141.4, 137.8, 133.7, 130.9, 129.1,
129.0, 127.8, 121.9, 106.4, 69.0, 26.5, 15.8. IR (KBr) ν 3150, 2160, 1710, 1668, 1632, 1607, 1571,
1501, 1457, 1405, 1374, 899, 755, 694 cm-1. HRMS m/z 345.0666 (M + Na+), Cal.
C18H14N2O2SNa+, 345.0668.
4.2.11 1-Methyl-4,6-diphenyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione
ꢀ2kꢁ
o
Yellow solid (46.7 mg, 61%); Melting range: 54.2-55.8 C;1H NMR (600 MHz, CDCl3) δ
7.47-7.33 (m, 6H), 7.16 (d, J = 7.8 Hz, 2H), 7.03 (d, J = 7.8 Hz, 2H), 6.63-6.62 (m, 2H), 6.49 (d, J
= 9.5 Hz, 1H), 2.94 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 184.3, 165.5, 158.1, 152.8, 144.5,
135.1, 133.1, 132.7, 131.4, 130.6, 129.2, 129.1, 129.0, 128.0, 126.9, 122.2, 106.0, 70.1, 26.5. IR
(KBr) ν 3057, 2164, 1706, 1672, 1649, 1603, 1580, 1500, 1454, 1374, 1362, 904, 769, 689 cm-1.
HRMS m/z 407.0829 (M + Na+), Cal. C23H16N2O2SNa+, 407.0825.
4.2.12
6-Methoxy-1-methyl-4-phenyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione
o
1
(2l) White solid (50.5 mg, 77%); Melting range: 231.8-232.9 C; H NMR (600 MHz, CDCl3) δ
7.45 (d, J = 7.1 Hz, 1H), 7.41 (t, J = 7.3 Hz, 2H), 7.19-7.11 (m, 2H), 6.44 (d, J = 9.8 Hz, 1H), 6.30
(d, J = 9.8 Hz, 1H), 5.77 (s, 1H), 3.74 (s, 3H), 2.85 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 185.4,
167.0, 165.7, 156.9, 138.9, 133.1, 131.0, 129.1, 128.7, 127.6, 122.4, 106.6, 106.3, 69.7, 56.5, 26.2.
IR (KBr) ν 3145, 2158, 1713, 1654, 1624, 1605, 1586, 1496, 1447, 1368, 1230, 992, 736, 687
cm-1. HRMS m/z 361.0620 (M + Na+), Cal. C18H14N2O3SNa+, 361.0617.
4.2.13 7-Chloro-1-methyl-4-phenyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (2m)
o
1
White solid (27.5 mg, 40%); Melting range: 155.8-157.2 C; H NMR (600 MHz, CDCl3) δ
7.50-7.43 (m, 3H), 7.22 (d, J = 7.4 Hz, 2H), 6.73 (d, J = 1.7 Hz, 1H), 6.60-6.54 (m, 2H), 2.98 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 176.5, 164.6, 155.9, 143.6, 138.7, 137.4, 132.9, 131.3, 129.3,
128.4, 127.8, 123.0, 105.8, 70.1, 26.8. IR (KBr) ν 3136, 2158,1730, 1675, 1624, 1595, 1578, 1497,
1447, 1378, 1328, 845, 736, 696 cm-1. HRMS m/z 365.0121 (M + Na+), Cal. C17H11ClN2O2SNa+,
365.0122.
4.2.14 7-Bromo-1-methyl-4-phenyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (2n)
o
1
White solid (41.8 mg, 54%); Melting range: 177.7-178.5 C; H NMR (600 MHz, CDCl3) δ
7.50-7.43 (m, 3H), 7.22 (d, J = 7.2 Hz, 2H), 7.01 (d, J = 2.5 Hz, 1H), 6.60-6.56 (m, 2H), 2.99 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 176.4, 164.6 155.7, 143.6, 143.0, 132.3, 131.3, 129.2, 129.1,
14

128.4, 127.8, 123.0, 105.8, 70.7, 26.8. IR (KBr) ν 3126, 2158, 1703, 1674, 1605, 1586, 1497,
1457, 1387, 1315, 884, 746, 696 cm-1. HRMS m/z 408.9619 (M + Na+), Cal. C17H11BrN2O2SNa+,
408.9617.
4.2.15 6-Chloro-1-methyl-4-phenyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (2o)
o
1
Yellowish solid (41.0 mg, 60%); Melting range: 187.1-188.8 C; H NMR (600 MHz, CDCl3) δ
7.48 (d, J = 7.1 Hz, 1H), 7.44 (t, J = 7.3 Hz, 2H), 7.25 (d, J = 7.4 Hz, 2H), 6.65 (d, J = 9.8 Hz, 1H),
6.56 (d, J = 9.6 Hz, 1H), 2.91 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 182.2, 165.2, 155.3, 149.1,
142.3, 133.4, 133.0, 131.3, 129.2, 128.1, 127.8, 124.1, 105.8, 71.5, 26.2. IR (KBr) ν 3136, 2148,
1703, 1674, 1632, 1619, 1586, 1497, 1447, 1368, 973, 736, 696 cm-1. HRMS m/z 365.0124 (M +
Na+), Cal. C17H11ClN2O2SNa+, 365.0122.
4.2.16 1'-Methyl-3'-phenyl-4'-thiocyanato-4H-spiro[naphthalene-1,2'-pyrrole]-4,5'(1'H)-dione (2p)
o
1
White solid (36.3 mg, 50%); Melting range: 218.1-218-9 C; H NMR (600 MHz, CDCl3) δ 8.17
(d, J = 7.7 Hz, 1H), 7.69 (t, J = 7.1 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H),
7.25-7.21 (m, 3H), 6.76 (d, J = 7.4 Hz, 2H), 6.65 (d, J = 10.1 Hz, 1H), 6.56 (d, J = 10.1 Hz, 1H),
2.81 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 182.5, 165.5, 160.8, 143.2, 135.6, 134.1, 133.8, 132.6,
130.8, 130.1, 128.9, 128.8, 127.8, 127.7, 125.8, 121.2, 106.5, 69.6, 26.3. IR (KBr) ν 3044, 2155,
1729, 1668, 1656, 1607, 1583, 1510, 1449, 1364, 1291, 840, 767, 709 cm-1. HRMS m/z 381.0668
(M + Na+), Cal. C21H14N2O2SNa+, 381.0667.
4.2.17 1-Ethyl-4-phenyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione[11e] (2q)
White solid (50.6 mg, 78%); Melting range: 142.3-144.2 oC; 1H NMR (600 MHz, CDCl3) δ 7.48 –
7.41 (m, J = 28.3, 3H), 7.23 (d, J = 7.3 Hz, 2H), 6.56 (d, J = 10.0 Hz, 2H), 6.49 (d, J = 9.9 Hz,
2H), 3.41 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 183.4,
164.9, 156.6, 143.4, 133.5, 131.0, 129.0, 128.9, 127.8, 122.8, 106.1, 68.9, 36.8, 15.0. IR (KBr) ν
3126, 2158, 1694, 1664, 1644, 1615, 1586, 1498, 1457, 1378, 1308, 865, 735, 696 cm-1. HRMS
m/z 345.0665 (M + Na+), Cal. C18H14N2O2SNa+, 345.0668.
4.2.18
1-Isopropyl-4-phenyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione
(2r)
o
1
Yellowish solid (59.4 mg, 88%); Melting range: 170.1-171.8 C; H NMR (600 MHz, CDCl3) δ
7.47-7.70 (m, 3H), 7.22 (d, J = 7.6 Hz, 2H), 6.60 (d, J = 10.0 Hz, 2H), 6.48 (d, J = 9.7 Hz, 2H),
3.53-3.47 (m, 1H), 1.46 (d, J = 6.8 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 183.4, 164.4, 155.7,
143.4, 133.4, 130.9, 129.0, 129.0 127.8, 123.6, 106.2, 69.6, 47.4, 20.8. IR (KBr) ν 3145, 2929,
2158, 1704, 1656, 1632, 1586, 1497, 1457, 1097, 1338, 865, 736, 696 cm-1. HRMS m/z 359.0827
(M + Na+), Cal. C19H16N2O2SNa+, 359.0825.
15

4.2.19 1-Benzyl-4-phenyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione[11e] (2s)
o
1
White solid (49.6 mg, 78%); Melting range: 142.1-143.7 C; H NMR (600 MHz, CDCl3) δ
7.45-7.16 (m, 11H), 6.33 (d, J = 9.9 Hz, 2H), 6.29 (d, J = 9.9 Hz, 2H), 4.59 (s, 2H); 13C NMR
(150 MHz, CDCl3) δ 183.4, 165.1, 157.3, 143.2, 136.6, 133.1, 131.0, 129.0, 129.0 128.7, 128.7,
128.2, 127.8, 122.5, 106.1, 68.7, 45.5. IR (KBr) ν 3166, 2929, 2168, 1717, 1656, 1632, 1583,
1497, 1447, 1387, 865, 736, 687 cm-1. HRMS m/z 407.0824 (M + Na+), Cal. C23H16N2O2SNa+,
407.0825.
4.2.20 1-Acetyl-4-phenyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (2t) Yellow
solid (30.2 mg, 45%); Melting range: 209.3-210.8 oC; 1H NMR (600 MHz, CDCl3) δ 7.49 (d, J =
7.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.14 (d, J = 7.4 Hz, 2H), 6.54 (d, J = 9.9 Hz, 2H), 6.43 (d, J
= 9.8 Hz, 2H), 2.66 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 183.3, 168.4, 163.8, 161.6, 141.9,
133.0, 131.5, 129.0, 128.0, 127.6, 122.3, 105.5, 68.6, 25.6. IR (KBr) ν 3145, 2168, 1729, 1693,
1680, 1619, 1607, 1583, 1506, 1447, 1387, 1328, 1259, 874, 844, 746, 687 cm-1. HRMS m/z
359.0464 (M + Na+), Cal. C18H12N2O3SNa+, 359.0461.
4.2.21 1,4-Dimethyl-3-thiocyanato-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (2u) Yellow solid
(32.9 mg, 57%); Melting range: 139.1-140.9 oC 1H NMR (600 MHz, CDCl3) δ 6.62 (d, J = 9.7 Hz,
2H), 6.36 (d, J = 9.8 Hz, 2H), 2.92 (s, 3H), 2.06 (s, 3H); 13C NMR (150MHz, CDCl3) δ 183.2,
165.4, 158.0, 143.5, 134.2, 121.4, 106.9, 68.8, 26.8, 12.2. IR (KBr) ν 3048, 2190, 1722, 1678,
1635, 1417, 1363, 1353, 863 cm-1. HRMS m/z 269.0365 (M + Na+), Cal. C12H10N2O2SNa+,
269.0366.
4.2.22 1-Phenyl-2-thiocyanato-6,7-dihydro-3H-pyrrolo[2,1-j]quinoline-3,9(5H)-dione (2v) Yellow
solid (39.4 mg, 50%); Melting range: 99.4-100.5 oC; 1H NMR (600 MHz, CDCl3) δ 7.56-7.53 (m,
3H), 7.40-7.39 (m, 1H), 7.27-7.26 (m, 2H), 7.07-7.04 (m, 2H), 4.38-4.36 (m, 2H), 3.05 (t, J = 6.0
Hz, 2H), 2.21-2.17 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 158.0, 155.5, 136.9, 135.4, 131.9,
129.3, 128.9, 128.5, 127.2 125.2, 122.3, 120.8, 117.1, 109.3, 43.8, 27.7, 20.6. IR (KBr) ν 3068,
2143, 1717, 1658, 1644, 1595, 1583, 1498, 1449, 1388, 899,731,694 cm-1. HRMS m/z 357.0667
(M + Na+), Cal. C19H14N2O2SNa+, 357.0668.
4.2.23 1-methyl-4-phenyl-3,8-dithiocyanato-1-azaspiro[4.5]deca-3,6,9-trien-2-one (3a) Yellow
solid; 1H NMR (600 MHz, DMSO-d6) δ 7.46-7.45 (m, 3H), 7.33-7.32(m, 2H), 6.32 (dd, J = 10.1,
3.1 Hz, 2H), 5.81 (dd, J = 10.1, 1.8 Hz, 2H), 4.52 (d, J = 1.7 Hz, 1H), 2.88 (s, 3H); 13C NMR (151
MHz, DMSO-d6) δ 165.0, 162.6, 131.8, 130.5, 129.0, 128.6, 127.4, 120.4, 111.9, 108.9, 66.8, 42.8,
16

26.6. IR (KBr) ν 3298, 2146, 2178, 1711, 1689, 1624, 1581, 1483, 1428, 1363, 1276, 831, 744,
690 cm-1. HRMS m/z 352.0572 (M + H+), Cal. C18H13N3OS2H+, 351.0573.
1
4.2.24 4-phenyl-3-thiocyanato-2H-chromen-2-one (6a) [19] White solid; H NMR (600 MHz,
CDCl3) δ 7.67 – 7.60 (m, 4H), 7.46 (d, J = 8.3, 1H), 7.34 – 7.29 (m, 2H), 7.28 – 7.23 (m, 2H),
7.16 (d, J = 8.0, 1H); 13C NMR (150 MHz, CDCl3) δ 160.8, 157.3, 153.6, 134.0, 133.2, 130.3,
129.6, 128.7, 128.0, 125.0, 119.9, 117.3, 112.9, 108.1 . IR (KBr) ν 3051, 2171, 1731, 1595, 1542,
1479, 1448, 1301, 987, 768, 694 cm-1.
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (Nos.
21672174 and 21977084), and the Natural Science Foundation of Chongqing (No.
cstc2019jcyj-msxmX0297).
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19

Highlights
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A visible-light-mediated metal-free thiocyanate radical addition/ipso-cyclization/oxidation
cascade reaction is described.
With this reaction, various thiocyanato-containing azaspirotrienediones were synthesized
from N-phenylpropynamides.
Cheap and readily available ammonium thiocyanate was used as a precursor to the
thiocyanate free radical.
The reaction completes the formation of C-S, C-C and C=O bonds in one pot, with air
oxygen as oxidant and oxygen source.

Declaration of Interest Statement
We declare no conflicts of interest.