A Palladium Iodide-Catalyzed Cyclocarbonylation Approach to Thiadiazafluorenones

Article abstract of DOI:10.1021/acs.joc.6b01028

The first example of an additive cyclocarbonylation process leading to 1-thia-4a,9-diazafluoren-4-ones is reported. This process is based on the reaction of readily available 2-(propynylthio)benzimidazoles with carbon monoxide carried out in EtOH at 100 °C under a 5/2 mixture of CO-CO₂ at 70 atm in the presence of the PdI₂/KI catalytic system. Experimental evidence suggests a mechanistic pathway involving N-palladation of the substrate followed by CO insertion, triple bond insertion, protonolysis, and isomerization.

Full text of DOI:10.1021/acs.joc.6b01028

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Note
A Palladium Iodide Catalyzed Cyclocarbonylation
Approach to Thiadiazafluorenones
Lucia Veltri, Veronica Paladino, Pierluigi Plastina, and Bartolo Gabriele
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01028 • Publication Date (Web): 16 Jun 2016
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A Palladium Iodide Catalyzed Cyclocarbonylation Approach to Thiadiazafluorenones
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Lucia Veltri,*,† Veronica Paladino,† Pierluigi Plastina,‡ and Bartolo Gabriele*,†
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† Laboratory of Industrial and Synthetic Organic Chemistry (LISOC), Department of Chemistry and Chemical
Technologies, University of Calabria, Via Pietro Bucci 12/C, 87036 Arcavacata di Rende (CS), Italy
‡ Department of Chemistry and Chemical Technologies, University of Calabria, Via Pietro Bucci 14/C, 87036 Arcavacata
di Rende (CS), Italy
lucia.veltri@unical.it; bartolo.gabriele@unical.it
Abstract
The first example of an additive cyclocarbonylation process leading to 1-thia-4a,9-diazafluoren-4-ones is
reported. It is based on the reaction of readily available 2-(propynylthio)benzimidazoles with carbon
monoxide carried out in EtOH at 100 °C under 70 atm of a 5/2 mixture of CO-CO2, in the presence of the
PdI2/KI catalytic system. Experimental evidences suggest a mechanistic pathway involving N-palladation of
the substrate followed by CO insertion, triple bond insertion, protonolysis and isomerization.
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Me
S
O
PdI2 (2 mol %)
KI (1 equiv)
N
N
N
S
+ CO
R
R
CO (50 atm)
CO2 (20 atm)
EtOH, 100 °C, 3 h
N
H
1
2 (65-74%)
PdI2
CO
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HI
I
IPd
O
O
O
Pd
HI
N
N
N
N
S
N
S
R
PdI2
S
R
R
N
1-Thiadiazafluoren-4-ones are an important class of polyheterocyclic compounds, known to possess
important pharmacological activities.1,2 In particular, some 1-thiazafluorenone derivatives have shown a
positive inotropic effect and a strong cardiotonic activity,2 while other derivatives are known to be anti-
hyper secretion agents.2 They are usually prepared by intramolecular amidation of 3-(1H-benzo[d]imidazol-
2-ylthio)propanoic acid and its derivatives.3 Clearly, the possibility to synthesize them by a direct
carbonylation procedure, involving the use of the simplest and most available C-1 unit (carbon monoxide),
would represent a very attractive alternative synthetic approach. Currently, cyclocarbonylation constitutes
a method of primary importance for the construction of a ring with direct incorporation of the carbonyl
group into the cycle starting from CO.4 In particular, palladium-catalyzed cyclocarbonylation reactions of
unsaturated substrates bearing a nucleophilic group in a suitable position for cyclization have proved to be
particularly significant for the synthesis of carbonylated heterocycles, with many important examples being
reported in the recent literature.4-6
In this Note, we wish to report a novel cyclocarbonylation route to 1-thia-4a,9-diazafluoren-4-one 2
starting from readily available 2-(prop-2-ynylthio)-1H-benzo[d]imidazoles 1.7 The process, catalyzed by a
simple catalytic system consisting of PdI2 in conjunction with KI and promoted by an excess of carbon
dioxide, corresponds to a 6-exo-dig carbonylative cyclization, in which the nitrogen of the imidazole ring of
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1 acts as nucleophile, followed by in situ isomerization of the ensuing double bond from the exocyclic to
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the endocyclic position (Scheme 1).
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Me
O
O
N
PdI2 cat
N
N
N
N
S
+ CO
R
S
R
S
R
N
H
1
2
Scheme 1. PdI2-catalyzed cyclocarbonylation of 2-(prop-2-ynylthio)-1H-benzo[d]imidazoles 1 followed by double bond
isomerization leading to 1-thia-4a,9-diazafluoren-4-one 2.
2-(Prop-2-ynylthio)-1H-benzo[d]imidazole 1a was used as model substrate for optimizing the reaction
conditions that would lead to the polyheterocyclic derivatives 2. This substrate was initially allowed to react
with carbon monoxide (30 atm) at 100 °C in MeOH as the solvent (1a concentration = 0.1 mmol per mL of
solvent), in the presence of PdI2 (2 mol %) and KI (1 equiv). After 3 h, substrate conversion was quantitative,
and analysis of the reaction mixture evidenced the formation of the desired product, 3-methyl-1-thia-4a,9-
diazafluoren-4-one 2a, in 37% yield, together with heavy unidentified compounds (chromatographically
immobile materials) (Table 1, entry 1).8 Although the yield of 2a was modest, this initial result confirmed
the possibility to realize the direct synthesis of a thiadiazafluorenone by a PdI2-catalyzed cyclocarbonylation
route. With the aim of improving the selectivity of 2a, we then changed the reaction parameters, such as
the nature of the catalyst, substrate concentration, reaction temperature, and solvent (Table 1). The use of
PdCl2/KCl instead of PdI2/KI led to less satisfactory results (Table 1, entry 2), while practically the same yield
of 2a was obtained by changing KI with diethylammonium iodide (Table 1, entry 3). On the other hand,
lower yields of 2a were observed using PdCl2(PPh3)2 (Table 1, entry 4) or a Pd(0) complex such as Pd(dba)2
(Table 1, entry 5). A lower yield was also observed with 10 mol % of KI rather than 1 equiv (Table 1, entry
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6), working at 80 °C rather than 100 °C (Table 1, entry 7), or using 2-(prop-2-ynylthio)-1H-
benzo[d]imidazolium bromide 1a’ as the substrate instead of 1a (Table 1, entry 8). Selectivity toward 2a
was instead improved working under more concentrated conditions (0.2 rather than 0.1 mmol of 1a per mL
of MeOH Table 1, entry 9) or under higher CO pressure (50 atm, Table 1, entry 10). Interestingly, the use of
a CO-CO2 mixture (30:20 atm) also tended to augment the product yield (Table 1, entry 11). The nature of
the solvent was also very important for product selectivity. In particular, the process worked well not only
in MeOH but also in another protic solvent such as EtOH (Table 1, entry 12), while less satisfactory results
were obtained in aprotic solvents such as dioxane, DME, MeCN, or DMA (Table 1, entries 13-16).
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Under the final optimized conditions, corresponding to 2 mol % of PdI2 and 1 equiv of KI, at 100 °C for 3
h in EtOH (1a concentration = 0.2 mmol per mL of solvent), under 70 atm of a CO/CO2 mixture (50/20 atm),
the desired thiadiazafluorenone was isolated in 65% isolated yield (Table 2, entry 1). The process was then
extended to differently substituted substrates 1b-f.
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Table 1. Carbonylation reaction of 2-(prop-2-ynylthio)-1H-benzo[d]imidazole 1a under different conditions.a
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Me
O
N
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8
9
N
N
Pd cat
S
+ CO
S
N
H
1a
2a
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Entry
Catalyst
Cocatalyst
T (°C)
Solvent
P(CO) (atm)
Yield of 2ab (%)
1
2
3
4
5
6
PdI2
PdCl2
KI (1 equiv)
100
100
100
100
100
100
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
30
30
30
30
30
30
37
14c
36
17
<5
30
KCl (1 equiv)
+ -
PdI2
Et2NH2 I (1 equiv)
PdCl2(PPh3)
Pd(dba)2
-
-
PdI2
PdI2
PdI2
PdI2
PdI2
PdI2
PdI2
PdI2
PdI2
PdI2
PdI2
KI (0.2 equiv)
KI (1 equiv)
KI (1 equiv)
KI (1 equiv)
KI (1 equiv)
KI (1 equiv)
KI (1 equiv)
KI (1 equiv)
KI (1 equiv)
KI (1 equiv)
KI (1 equiv)
80
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
30
30
30
50
30
30
30
30
30
30
25d
18e
40f
45
53g
44
0
7
8
100
100
100
100
100
100
100
100
100
9
10
11
12
13
14
15
16
dioxane
DME
0
MeCN
DMA
12
10
a Unless otherwise noted, all reactions were carried out under 30 atm of CO (at 25 °C) for 3 h with a substrate
concentration of 0.1 mmol of 1a per mL of solvent, in the presence of 2 mol % of the palladium catalyst.
b
Unless otherwise noted, substrate conversion was quantitative.
Isolated yield based on starting 1a.
d
c
Substrate conversion was 76%, by isolation of unreacted substrate. Substrate conversion was 68%, by
e
isolation of unreacted substrate.
benzo[d]imidazolium bromide 1a’ as the substrate instead of 1a. The reaction was carried out with a
substrate concentration of 0.2 mmol per mL of solvent. The reaction was carried out under 50 atm (at 25
°C) of a 3:2 mixture of CO-CO2.
The reaction was carried out using 2-(prop-2-ynylthio)-1H-
f
g
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Table 2. Synthesis of 1-thia-4a,9-diazafluoren-4-one 2 by PdI2-catalyzed cyclocarbonylation of 2-(prop-2-ynylthio)-1H-
benzo[d]imidazoles 1.a
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Me
O
PdI2 (2 mol %)
KI (1 equiv)
N
N
S
+ CO
R
S
R
CO (50 atm)
CO2 (20 atm)
N
H
N
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1
2
EtOH, 100 °C, 3 h
Entry
1
2
Yield of 2b (%)
Me
S
1
2
3
4
5
65
O
N
N
N
S
N
H
1a
2a
Me
72
71
O
Me
Me
N
Me
Me
N
N
S
S
N
H
1b
2b
Me
S
O
Cl
Cl
N
Cl
Cl
N
N
S
N
H
1c
2c
Me
67
O
MeO
MeO
N
MeO
MeO
N
N
S
S
N
H
1d
2d
74c
Me
S
O
MeO
N
N
N
S
MeO
N
H
1e
2e
Me
6
68d,e
O
F
N
N
N
S
S
F
N
H
1f
2f
a Unless otherwise noted, all reactions were carried out at 100 °C for 3 h in EtOH as the solvent (0.2 mmol of 1 per mL
of EtOH) under 70 atm of a 5:2 mixture of CO-CO2 (at 25 °C), in the presence of PdI2 (2 mol %) in conjunction with KI (1
equiv). Substrate conversion was quantitative in all cases. The formation of heavy products (chromatographically
immobile materials) accounted for the difference between product yield and substrate conversion. Isolated yield
based on starting 1. c Mixture of regioisomers (ca. 1.2:1, by GLC). d Mixture of regioisomers (ca. 1.4:1, by H NMR).
b
1
e
The reaction was carried out with 5 mol % of PdI2 for 15 h
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As can be seen from the results shown in Table 2, entries 2-6, the process was quite general, as it
worked nicely with substrates bearing electron-withdrawing groups as well as electron-donating groups on
the aromatic ring. 5-fluoro-2-(prop-2-ynylthio)-1H-benzo[d]imidazole 1f was less reactive than the other
substrate tested, thus its carbonylation was carried out for 15 h with a 5 mol % of PdI2 (Table 2, entry 6).
Quite predictably on the basis of the similar reactivity of the two nitrogens of the benzimidazole ring
because of conjugation, a mixture of regioisomers was formed starting from monosubstituted substrates
1e and 1f (Table 2, entries 5 and 6, respectively).
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Based on our experience on PdI2/KI-catalyzed carbonylation reactions,5a,5c,9 and on the experimental
results obtained in this work, we can propose the mechanism shown in Scheme 2 for rationalizing the
formation of thiadiazafluorenones 2 from (propynylthio)benzimidazoles 1 under our conditions (anionic
iodide ligands are omitted for clarity). The fact that practically no reaction occurs with a classical Pd(0)
catalyst, such as Pd(dba)2 (Table 1, entry 4), seems to rule out a Pd(0)-mediated mechanism, initiated by
oxidative addition of the N-H group of the substrate to a Pd(0) species formed in situ under the reaction
conditions. Accordingly, a Pd(II)-catalyzed process, initiated by N-palladation of 1 with PdI2 to give complex
I and HI, appears much more likely (Scheme 2). Carbon monoxide insertion into the N-Pd bond of I would
lead to carbamoylpalladium intermediate II, from which the final product would be obtained by triple bond
insertion to give III, protonolysis by HI (leading to intermediate IV), and isomerization. This mechanistic
hypothesis is also in agreement with the higher activity displayed by the PdI2/KI system with respect to
PdCl2/KCl, because, on one hand, iodide is a better leaving group in the N-palladation step and, on the
other hand, HI is a stronger acid in the protonolysis step.10 The importance of an effective protonolysis step
with regeneration of the Pd(II) catalyst is further demonstrated by the experimental observation that the
process works much better in protic solvents, where HI dissociation is more favored, rather than in aprotic
ones. Finally, although the favorable effect exerted by CO2 is difficult to interpret, the excess CO2 may also
favor the protonolysis step by slightly augmenting the acidity of the reaction medium. It may also act as
ligand to Pd(II),11 suitably stabilizing the key organometallic intermediates leading to 2.
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I
I
O
Pd
Pd
N
N
N
PdI2
HI
CO
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S
S
S
R
R
R
N
N
N
H
I
II
1
IPd
O
Me
S
O
O
N
N
HI
PdI2
N
N
N
N
S
R
S
R
R
III
2
IV
Scheme 2. Proposed mechanistic pathway for the PdI2-catalyzed cyclocarbonylation of 2-(prop-2-ynylthio)-1H-
benzo[d]imidazoles 1 leading to 1-thia-4a,9-diazafluoren-4-one 2.
In conclusion, we have developed a novel cyclocarbonylative method for the direct synthesis of
thiadiazafluorenones 2 starting from readily available (propynylthio) benzimidazoles 1. The process,
catalyzed by the simple catalytic system PdI2/KI, occurs in EtOH under relatively mild conditions (100 °C, 70
atm of a 5:2 mixture of CO-CO2) and takes place through an ordered sequence of steps involving N-
palladation, CO insertion, triple bond insertion, protonolysis, and isomerization. To the best of our
knowledge, this is the first example of synthesis of polyheterocycles 2 by a direct additive carbonylation
approach.
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Experimental Section
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General Experimental Methods. Solvent and chemicals were reagent grade and were used without
further purification. All reactions were analyzed by TLC on silica gel 60 F254 and by GLC using capillary
columns with polymethylsilicone + 5% phenylsilicone as the stationary phase. Column chromatography was
performed on silica gel 60 (70-230 mesh) or alumina gel 90 (70-230 mesh). Evaporation refers to the
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removal of solvent under reduced pressure. Melting points are uncorrected. H NMR and C NMR spectra
were recorded at 25 °C on a 300 or 500 MHz Spectrometers in CDCl3, DMSO-d6, or CD3OD solutions, with
19
Me4Si as internal standard. F NMR spectra were recorded at 25 °C on a 500 MHz Spectrometer in CDCl3
solutions at 471 MHz with CF2Br2 or CFCl3 as internal standard. Chemical shifts () and coupling constants (J)
are given in ppm and in Hz, respectively. IR spectra were taken with an FT-IR spectrometer. Mass spectra
were obtained using a GC-MS apparatus at 70 eV ionization voltage and by electrospray ionization using an
ESI-MS spectrometer. The LC-MS was operated in the positive ion mode. The experimental conditions were
as follows: ion spray voltage 4000 V; curtain gas 35 psi; temperature 25 °C; ion source gas 15 psi;
declustering and focusing potentials 50 and 400 V, respectively. Microanalyses were carried out in our
analytical laboratory.
Preparation of Substrate Precursors. Starting materials 1,3-dihydrobenzimidazole-2-thiones were
commercially available, except for 5,6-dimethoxy-1,3-dihydrobenzimidazole-2-thione and 5-fluoro-1,3-
dihydrobenzimidazole-2-thione, which were prepared according to the following procedure:12 to a three-
necked flask were introduced, under nitrogen, 4-fluorobenzene-1,2-diamine (2.0 g, 16.0 mmol) or 1,2-
diamino-4,5-dimethoxybenzene13 (2.7 g, 16.0 mmol), carbon disulfide (2.4 g, 32.0 mmol) and a solution of
KOH (1.8 g, 32 mmol) in anhydrous EtOH (26 mL). The mixture was refluxed with stirring for 4 h. After
cooling, glacial acetic acid (30 mL) was added to the mixture. The solvent was evaporated, and to the solid
residue was added aq NaOH (2.5 wt %, 200 mL) containing a few drops of NaHSO3. The mixture was
refluxed until dissolution of the solid was observed, and, after cooling at 0°C, the pH of the solution was
adjusted to neutrality by addition of conc HCl. To the resulting mixture was added AcOEt (100 mL), phases
were separated and the aqueous phase was extracted with AcOEt (3  50 mL). The collected organic layers
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were dried over Na2SO4. After filtration and evaporation of the solvent, the product was purified by column
chromatography on silica gel using 6:4 hexane AcOEt for 5-fluoro-1,3-dihydrobenzimidazole-2-thione and
7:3 hexane-acetone for 5,6-dimethoxy-1,3-dihydrobenzoimidazole-2-thione.
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5-Fluoro-1,3-dihydrobenzimidazole-2-thione. Yield: 2.2 g, starting from 2 g of 4-Fluorobenzene-1,2-
diamine (80 %). Yellow solid, mp = 227-229°C. IR (KBr): ν = 1630 (m), 1503 (s), 1471 (m), 1344 (s), 1252 (m),
1
1194 (m), 1145 (s), 985 (m), 837 (s), 703 (s), 658 (s) cm–1; H NMR (300 MHz, CD3OD): δ = 7.20 -7.11 (m, 1
13
H), 7.00 – 6.86 (m, 2 H); C NMR (75 MHz, CD3OD): δ = 170.9, 161.1 (d, J = 239), 134.4 (d, J = 13), 130.3,
111.6 (d, J = 10), 111.1 (d, J = 25), 98.3 (d, J = 29); 19F NMR (471 MHz, CD3OD):  = - 119.9 (s, 1 F); MS (ESI+,
direct infusion): m/z = 169 [(M+H)+]; anal. calcd for C7H5FN2S (168.19): C, 49.99; H, 3.00; F, 11.30; N, 16.66;
S, 19.06; found C, 49.97; H, 3.02; F, 11.28; N, 16.61; S, 19.12.
5,6-Dimethoxy-1,3-dihydrobenzimidazole-2-thione. Yield: 2.0 g, starting from 2.69 g of 1,2-diamino-4,5-
dimethoxybenzene (60 %). Yellow solid, mp = 289-290°C, lit.12b 289-290 °C. IR (KBr): ν = 2360 (m), 1638 (m),
1510 (s), 1472 (m), 1460 (m), 1350 (s), 1249 (m), 1212 (m), 1186 (m), 1150 (m), 1014 (m), 901 (m), 829 (m),
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729 (m) cm–1; H NMR (300 MHz, DMSO-d6): δ = 12.31 (s, br, 2 H), 6.75 (s, 2 H), 3.76 (s, 6 H); C NMR (75
MHz, DMSO-d6): δ = 166.1, 145.9, 125.4, 94.5, 56.0; MS (ESI+, direct infusion): m/z = 211 [(M+H)+]; anal.
calcd for C9H10N2O2S (210.25): C, 51.41; H, 4.79; N, 13.32; S, 15.25; found C, 51.60; H, 4.81; N, 13.29; S,
15.22.
Preparation of 2-(Prop-2-ynylthio)-1H-benzo[d]imidazoles 1.14 To a solution of the 1,3-
dihydrobenzimidazole-2-thione derivative (16.7 mmol) [1,3-dihydrobenzimidazole-2-thione: 2.50 g; 5,6-
dimethyl-1,3-dihydrobenzimidazole-2-thione: 2.97 g; 5,6-dichloro-1,3-dihydrobenzimidazole-2-thione: 3.65
g; 5,6-dimethoxy-1,3-dihydrobenzimidazole-2-thione: 3.51 g; 5-methoxy-1,3-dihydrobenzimidazole-2-
thione: 3.00 g; 5-fluoro-1,3-dihydrobenzimidazole-2-thione: 2.81 g] in anhydrous acetone (100 mL), was
added, under nitrogen, K2CO3 (2.3 g, 16.7 mmol) followed by propargyl bromide (2.96 g, corresponding to
2.8 mL of a 80 wt. % solution in toluene, 25.1 mmol). The mixture was stirred at room temperature for 20 h.
After evaporation of the solvent, dichloromethane (30 mL) and water (30 mL) were sequentially added and
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the phases were separated. The aqueous phase was extracted again with dichloromethane (20 mL) and
finally the collected organic phases were dried over Na2SO4. After filtration and evaporation of the solvent,
products 1a-f were purified by column chromatography on silica gel using as eluent 9:1 hexane-AcOEt for
1a–c and 1e and 7:3 hexane-AcOEt for 1d and 1f. 2-(Prop-2-ynylthio)-1H-benzo[d]imidazolium bromide 1a’
was prepared as we already reported.12b
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2-(Prop-2-ynylthio)-1H-benzo[d]imidazole (1a). Yield: 2.51 g, starting from 2.50 g of 1,3-
dihydrobenzimidazole-2-thione (80%). Colorless solid, mp = 165 – 167 °C, lit.15 164-165 °C and 165-16712b;
IR (KBr) ν = 3048 (m), 2958 (m), 2888 (m), 2106 (vw), 1506 (w), 1444 (m), 1405 (s), 1351 (m), 1267 (m), 1227
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(m), 1012 (m), 977 (m), 745 (s), 657 (m)cm-1; H NMR (300 MHz, DMSO-d6) δ = 12.7 (s, br, 1 H), 7.56-7.42
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(m, 2 H), 7.21-7.10 (m, 2 H), 4.16 (d, J = 2.6, 2 H), 3.22 (t, J = 2.6, 1 H); C NMR (75 MHz, DMSO-d6) δ =
148.3, 121.5, 114.3 (br), 80.0, 73.9, 19.7; MS (ESI+, direct infusion): m/z = 189 [(M+H)+]; anal. calcd for
C10H8N2S (188.25): C, 63.80; H, 4.28; N, 14.88; S, 17.03; found C, 63.89; H, 4.30; N, 14.85; S, 16.96.
5,6-Dimethyl-2-(prop-2-ynylthio)-1H-benzo[d]imidazole (1b). Yield: 3.25 g, starting from 2.97 g of 5,6-
dimethyl-1,3-dihydrobenzimidazole-2-thione (90%). Colorless solid, mp = 163 – 164 ° C; IR (KBr) ν = 3051
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(m), 2920 (m), 2122 (vw), 1451 (s), 1415 (m), 1389 (s), 1299 (w), 1234 (w), 974 (m), 854 (m) cm-1; H NMR
(300 MHz, CD3OD) δ = 7.24 (s, 2 H), 4.92 (s, br, 1 H), 3.99-3.93 (m, 2 H), 2.65-2.57 (m, 1 H), 2.32 (s, 6 H); 13C
NMR (75 MHz, CD3OD) δ = 148.5, 139.2, 132.8, 115.4, 79.8, 73.2, 22.3, 20.2; MS (ESI+, direct infusion): m/z =
217 [(M+H)+]; anal. calcd for C12H12N2S (216.30): C, 66.63; H, 5.59; N, 12.95; S, 14.82; found C, 66.29; H,
5.61; N, 12.90; S, 15.20.
5,6-Dichloro-2-(prop-2-ynylthio)-1H-benzo[d]imidazole (1c). Yield: 3.21 g, starting from 3.65 g of 5,6-
dichloro-1,3-dihydrobenzimidazole-2-thione (75%). Colorless solid, mp = 185 – 188 °C; IR (KBr) ν = 3270 (m),
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2923 (m), 2122 (w), 1492 (w), 1402 (m), 1332 (m), 1260 (m), 1095 (m), 967 (m), 866 (m), 660 (s) cm-1; H
NMR (300 MHz, CD3OD) δ = 7.60 (s, 2 H), 4.92 (s, br, 1 H), 4.07 (d, J = 2.6, 2 H), 2.68 (t, J = 2.6, 1 H); 13C NMR
(75 MHz, CD3OD) δ = 153.5, 140.3, 127.4, 116.5, 79.2, 73.5, 21.6; MS (ESi+, direct infusion): m/z = 257
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[(M+H)+]; anal. calcd for C10H6Cl2N2S (257.139): C, 46.71; H, 2.35; Cl, 27.57; N, 10.89; S, 12.47; found C,
46.79; H, 2.33; Cl, 27.61; N, 10.86; S, 12.41.
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5,6-Dimethoxy-2-(prop-2-ynylthio)-1H-benzo[d]imidazole (1d). Yield: 3.43 g, starting from 3.51 g of 5,6-
dimethoxy-1,3-dihydrobenzimidazole-2-thione(83%). Yellow solid, mp = 95 – 97 ° C; IR (KBr) ν = 3287 (m),
2116 (w), 1665 (m),1632 (m), 1597 (m), 1511 (m), 1497 (m), 1453 (m), 1368 (m), 1339 (m), 1243 (m), 1216
(m), 1147 (m), 1012 (m ), 989 (m), 857 (m), 734 (s) cm-1; 1H NMR (300 MHz, DMSO-d6) δ = 12.45 (s, br, 1 H),
7.03 (s, 2 H), 4.06 (d, J = 1.9, 2 H), 3.77 (s, 6 H), 3.22 – 3.16 (m, 1 H); 13C NMR (75 MHz, DMSO-d6) δ = 146.2,
144.9, 133.5, (br), 97.2 (br), 80.2, 73.9, 55.9, 20.5; MS (ESI+, direct infusion): m/z = 249 [(M+H)+]; anal. calcd
for C12H12N2O2S (248.30): C , 58.05; H, 4.87; N, 11.28; S, 12.91; found C, 57.91; H, 4.89; N, 11.26; S, 12.88.
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5-Methoxy-2-(prop-2-ynylthio)-1H-benzo[d]imidazole (1e). Yield: 2.20 g, starting from 3.00 g of 5-
methoxy-1,3-dihydrobenzimidazole-2-thione (60%). Colorless solid, mp = 140 – 142 °C; IR (KBr) ν = 3262
(m), 2122 (vw), 1622 (m), 1456 (m), 1396 (s), 1342 (m), 1301 (m), 1272 (w), 1227 (m), 1158 (m), 1113 (w),
981 (m), 815 (m) cm-1; 1H NMR (300 MHz, DMSO-d6) δ = 12.6 (s, br, 1 H), 7.50-7.34 (m, 1 H), 7.17-6.93 (m, 1
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H), 6.81 (dd, J = 8.6, 2.3, 1 H), 4.15 (d, J = 2.5, 2 H), 3.79 (s, 3 H), 3.22 (t, J = 2.5, 1 H); C NMR (75 MHz,
DMSO-d6) δ = 155.4, 147.0, 137.1, 117.9, 110.7, 100.2, 94.5, 80.1, 73.9, 55.4, 20.0; MS (ESI+, direct infusion):
m/z = 219 [(M+H)+]; anal. calcd for C11H1oN2OS (218.27): C , 60.53; H, 4.62; N, 12.83; S, 14.69; found C,
60.32; H, 4.60; N, 12.88; S, 14.72.
5-Fluoro-2-(prop-2-ynylthio)-1H-benzo[d]imidazole (1f). Yield: 2.10 g, starting from 2.81 g of 5-fluoro-1,3-
dihydrobenzimidazole-2-thione (61%). Yellow solid, mp = 132 – 134 °C; IR (KBr) ν = 3303 (m) 1633 (m), 1498
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(s), 1461 (m), 1427 (m), 1362 (m), 1274 (m), 1242 (m), 1159 (m), 997 (m), 860 (m), 677 (m) cm-1; H NMR
(300 MHz, CD3OD) δ = 7.44 (dd, J = 8.8, 4.7, 1 H), 7.20 (dd, J = 9.1, 2.3, 1 H), 7.06 – 6.92 (m, 1 H), 4.06 – 4.01
(m, 2 H), 2.69 – 2.63 (m, 1 H); 13C NMR (75 MHz, CD3OD) δ = 161.1 (d, J = 238), 151.5, 141.1 (br), 137.4 (br),
116.0 (br), 111.5 (d, J = 26), 101.4 (d, J = 26), 79.8, 73.5, 73.4, 22.0; 19F NMR (471 MHz, CD3OD):  = - 113.5
(s); MS (ESI+, direct infusion): m/z = 207 [(M+H)+]; anal. calcd for C10H7FN2S (206.24): C , 58.24; H, 3.42; F,
9.21; N, 13.58; S, 15.55; found C, 58.29; H, 3.40; F, 9.18; N, 13.61; S, 15.52.
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General Procedure for the Synthesis of Thiadiazafluorenones 2a-f (Table 2). A 250 mL stainless steel
autoclave was charged in the presence of air with PdI2 (5.8 mg, 1.61  10–2 mmol, for 1a-e, 14.6 mg, 4.05 ×
10–2 mmol for 1f), KI (134.0 mg, 0.81 mmol), anhydrous EtOH (4.0 mL), the 2-(prop-2-ynylthio)-1H-
benzo[d]imidazole (0.81 mmol) (1a: 153 mg; 1b: 175 mg; 1c: 208 mg; 1d: 201 mg; 1e: 177 mg; 1f: 167 mg).
The autoclave was purged at room temperature several times with CO2 with stirring (5 atm) end eventually
pressurized with CO2 (20 atm) and CO (up to 70 atm). After being stirred at 100 °C for 3 h (for 1a-e) or 15 h
(for 1f), the autoclave was cooled, degassed and opened. After evaporation of the solvent, products 2 were
purified by column chromatography on alumina using 9:1 hexane-AcOEt (2b, 2c) or 8:2 hexane-AcOEt (2a,
2e, 2d, 2f) as eluent.
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3-Methyl-1-thia-4a,9-diazafluoren-4-one (2a). Yield: 114 mg, starting from 153 mg of 1a (65%) (Table 2,
entry 1). Colorless solid, mp = 170 – 172°C. IR (KBr): ν = 1680 (s), 1639 (m), 1618 (m), 1472 (m), 1401 (m),
1360 (m), 1310 (m), 1200 (w), 771 (m) cm-1; 1H NMR (300 MHz,CDCl3): δ = 8.54 (d, J = 7.8, 1 H), 7.76 (d, J =
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7.7, 1 H), 7.54-7.36 (m, 2 H), 6.56-6.51 (m, 1 H), 2.48 (d, J = 0.9, 3 H); C NMR (75 MHz, CDCl3) δ = 159.6,
148.8, 146.7, 142.5, 131.2, 125.8, 124.2, 118.6, 116.1, 115.6, 22.8; GC /MS: m/z= 216 (M+, 100), 188 (29),
175 (4), 150 (33), 143 (6), 129 (4), 122 (5), 108 (4), 90 (9); anal. calcd for C11H8N2OS (216.26): C, 61.09; H,
3.73; N 12.95; S, 14.83; found C, 61.35; H, 3.71; N 12.91; S, 14.89.
3,6,7-Trimethyl-1-thia-4a,9-diazafluoren-4-one (2b). Yield: 142 mg, starting from 175 mg of 1b (72%)
(Table 2, entry 2). Colorless solid, mp = 115 – 121°C. IR (KBr): ν = 1677 (s), 1377 (m), 1347 (m), 1315 (m),
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1286 (m), 1184 (m), 1094 (w), 846 (m) cm-1; H NMR (300 MHz, CDCl3) δ= 8.24 (s, 1 H), 7.45 (s, 1 H), 6.48-
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6.43, (m, 1 H), 2.44 (d, J = 1.1, 3 H), 2.39 (s, 3 H), 2.38 (s, 3 H); C NMR (75 MHz, CDCl3) δ = 159.6, 148.2,
145.6, 141.6, 134.9, 133.5, 130.0, 119.0, 116.1, 115.8, 22.5, 20.2; GC/MS: m/z = 244 (M+, 100), 229 (20), 216
(16), 201 (7), 178 (23), 163 (10), 157 (3), 122 (7), 91 (7), 67 (10); anal. calcd for C13H12N2OS (244.31): C,
63.91; H, 4.95; N 11.47; S, 13.12; found C, 63.80; H, 4.96; N 11.49; S, 13.09.
6,7-Dichloro-3-methyl-1-thia-4a,9-diazafluoren-4-one (2c). Yield: 164 mg, starting from 208 mg of 1c
(71%) (Table 2, entry 3). Yellow solid, mp = 153 – 155°C. IR (KBr):  = 1692 (s), 1467 (w), 1375 (m), 1340 (m),
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1297 (m), 1190 (m), 1095 (m), 842 (m) cm-1; H NMR (300 MHz, CDCl3): δ = 8.64 (s, 1 H), 7.82 (s, 1 H), 6.56
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(q, J = 1.2, 1 H), 2.52 (d, J = 1.2, 3 H); C NMR(75 MHz, CDCl3): δ = 153.5, 140.3, 127.4, 116.5, 79.2, 73.5,
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21.6; GC/MS: m/z = 286 [(M + 2)+, 69], 284 (M+, 100), 258 (23), 256 (33), 220 (18), 218 (25), 199 (3), 181 (8),
158 (4), 142 (4), 100 (4), 88 (6), 67 (61); anal. calcd for C11H6Cl2N2OS (285.15): C, 46.33; H, 2.12; Cl, 24.87; N
9.82; S, 11.24; found C, 46.21; H, 2.14; N 9.86; S, 11.27.
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6,7-Dimethoxy-3-methyl-1-thia-4a,9-diazafluoren-4-one (2d). Yield: 150 mg, starting from 201 mg of 1d
(67%) (Table 2, entry 4). Yellow solid, mp = 187 – 188°C. IR (KBr): ν = 1678 (s), 1465 (s), 1436 (s), 1340 (m),
1307 (m), 1193 (m), 1153 (m), 1016 (m), 862 (m), 830 (m) cm-1; 1H NMR (300 MHz, CDCl3): δ = 8.02 (s, 1 H),
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7.18 (s, 1 H), 6.48 (s, 1 H), 3.99 (s, 3 H), 3.96 (s, 3 H), 2.47 (s, 3 H); C NMR (75 MHz, CDCl3): δ = 159.7,
149.6, 148.4, 144.2, 137.1, 132.2, 125.4, 115.5, 101.7, 100.0, 56.9, 56.6, 22.5; GC/MS: m/z = 276 (M+, 100),
261 (28), 233 (6), 207 (11), 193 (5), 167 (5), 135 (5), 73 (6); anal. calcd for C13H12N2O3S (276.31): C, 56.51; H,
4.38; N 10.14; S, 11.60; found C, 56.66; H, 4.36; N 10.17; S, 11.64.
Mixture of 6-Methoxy-3-methyl-1-thia-4a,9-diazafluoren-4-one and 7-Methoxy-3-methyl-1-thia-4a,9-
diazafluoren-4-one (1.2:1 mixture of isomers A:B, by GLC) (2e). Yield: 148 mg, starting from 177 mg of 1e
(74%) (Table 2, entry 5). Yellow solid, mp = 125 – 130°C. IR (KBr): ν = 1689 (s), 1594 (w), 1478 (s), 1432 (m),
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1366 (m), 1303 (m), 1277 (m), 1200 (m), 1155 (m), 1023 (m), 839 (m) cm-1; H NMR (300 MHz,CDCl3): δ =
8.37 (d, J = 9.0, A), 8.05 (d, J = 2.5, B), 7.61 (d, J = 8.8, B), 7.19 (d, J = 2.4, 1 H, A), 7.07 (dd, J = 8.8, 2.5, 1 H,
B), 7.01 (dd, J = 9.0, 2.4, A), 6.51 (q, J = 1.1, 1 H, B), 6.48 (q, J = 1.1, 1 H, A), 3.91 (s, 3 H, B), 3.88 (s, 3 H, A),
2.48 (d, J = 1.2, 3 H, A), 2.47 (d, J = 1.1, 3 H, B) (Note: The A/B isomer assignments is based on 1H NMR peak
integration data: A refers to the major isomer, B to the minor); 13C NMR (75 MHz, CDCl3) δ = 159.5, 158.79,
158.75, 157.5, 149.1, 148.5, 147.1, 144.9, 135.3, 131.7, 130.9, 128.8, 125.0, 118.5, 116.7, 115.7, 115.4,
114.1, 100.3, 99.5, 56.0, 55.8, 29.7, 22.8; GC/MS [A (major isomer)]: m/z = 246 (M+, 100), 231 (42), 218 (7),
203 (14), 180 (21), 165 (29), 152 (4), 137 (4), 67 (36); GC/MS [B (minor isomer)]: m/z = 246 (M+, 100), 231
(41), 218 (9), 203 (10), 180 (15), 165 (27), 152 (4), 137 (6), 123 (3), 89 (4), 67 (34); anal. calcd for
C12H10N2O2S (246.28): C, 58.52; H, 4.09; N 11.37; S, 13.02; found C, 58.37; H, 4.07; N 11.39; S, 13.05.
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Mixture of 6-Fluoro-3-methyl-1-thia-4a,9-diazafluoren-4-one and 7-Fluoro-3-methyl-1-thia-4a,9-
diazafluoren-4-one (1.4:1 mixture of isomers A:B, by 1H NMR) (2f). Yield: 129 mg, starting from 167 mg of 1f
(68%) (Table 2, entry 6). Colorless solid, mp = 125 – 128°C. IR (KBr): ν = 1679 (s), 1466 (s), 1429 (s), 1355
(m), 1305 (m),1135 (m), 958 (m), 862 (m), 813 (m) cm-1; 1H NMR (300 MHz, CDCl3) δ = 8.47 (dd, J = 9.0, 5.0,
1 H, A), 8.24 (dd, J = 8.8, 2.4, 1 H, B), 7.67 (dd, J = 8.9, 4.8, 1 H, B), 7.40 (dd, J = 8.6, 2.3, 1 H, A), 7.28-7.09
(m, 1 H, A + 1 H, B), 6.55 (s, br, 1 H, A), 6.52 (s, br, 1 H, B), 2.51, (s, 3 H, A + 3 H, B) (Note: The A/B isomer
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assignments is based on H NMR peak integration data: A refers to the major isomer, B to the minor); C
NMR (75 MHz, CDCl3) δ = 160.9 (d, J = 243), 159.8 (d, J = 243), 159.4, 159.3, 149.3, 148.9, 143.3 (d, J = 12.5),
138.3 (d, J = 1.4), 131.1 (d, J = 13.9), 127.6 (d, J = 1.4), 119.2 (d, J = 9.7), 116.8 (d, J = 9.7), 115.5, 115.3,
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114.1 (d, J = 25.0), 112.2 (d, J = 25.0), 104.8 (d, J = 25.0), 103.3 (d, J = 29.8), 22.9, 22.8; F NMR (471 MHz,
CDCl3):  = - 108.5 (s), -109.7 (s); GC/MS [A + B]: m/z = 234 (M+ , 100), 206 (32), 191 (3), 168 (32), 162 (8),
147 (5), 136 (4), 108 (16), 95 (5); anal. calcd for C11H7FN2OS (234.25): C, 56.40; H, 3.01; F 8.11; N, 11.96; S,
13.69; found C, 56.29; H, 3.02; N 11.99; S, 13.65.
Supporting Information. Copies of 1H NMR, 13C NMR, and 19F NMR spectra for all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
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REFERENCES
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(1) (a) Garaliene, V.; Labanauskas, L.; Brukštus, A. Drug Res. 2006, 56, 282-287. (b) Brukshtus, A. B.;
Garalene, V. N.; Sirvidite, A. R.-R.; Daukshas, V. K. Pharm. Chem. J. 1994, 28, 392-395. (c) Brukshtus, A. B.;
Garalene, V. N.; Sirvidite, A. R.-R.; Daukshas, V. K. Pharm. Chem. J. 1993, 26, 851-854.
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(2) Crossley, R. (John Wyeth & Brother Limited, Maidemhead, England), US Pat. 4,873,237 (1989).
(3) See, for examples: (a) Khalil, A. K. Phosphorus Sulfur Silicon Relat. Elem. 2007, 182, 815-823. (b)
Britsun, V. N.; Lozinskii, M. O. Chem. Heterocycl. Compds. 2003, 39, 960-964. (c) Bell, S. C.; Wei, P. H. L. J.
Med. Chem. 1976, 19, 524-530.
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(4) Modern Carbonylation Methods; Kollar, L., Ed.; Wiley: Weinheim, 2008.
(5) For selected recent reviews, see: (a) Gabriele, B.; Salerno, G. Cyclocarbonylation. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, 2002; Vol.
2, pp 2623-2641. (b) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Rev. 2013, 113, 1-35. (c) Gabriele, B.;
Mancuso, R.; Salerno, G. Eur. J. Org. Chem. 2012, 6825-6839.
(6) For some very recent examples, see: (a) Mancuso, R.; Raut, D. S.; Marino, N.; De Luca, G.; Giordano,
C.; Catalano, S.; Barone, I.; Andò, S.; Gabriele, B. Chem. – Eur. J. 2016, 22, 3053-3064. (b) H. Yu, G. Zhang, H.
Huang, Angew. Chem. Int. Ed. 2015, 54, 10912-10916. (c) Veltri, L.; Mancuso, R.; Altomare, A.; Gabriele, B.
ChemCatChem 2015, 7, 2206-2213.
(7) Substrates 1 were easily prepared by propargylation of 1,3-dihydrobenzimidazole-2-thiones, as
described in the Experimental Section.
(8) A blank experiment, carried out on 1a under the same conditions as those of entry 1 (Table 1), but in
the absence of carbon monoxide, resulted in partial substrate decomposition. On the other hand, when
product 2a was heated under the same conditions as those of entry 1 (Table 1), it could be recovered
practically unreacted. These results show that 2a was stable under the reaction conditions, and that the
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formation of chromatographically immobile materials observed in the carbonylation reaction of 1a
reported in entry 1 (Table 1) must be due to partial substrate decomposition rather than product instability.
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(9) (a) Gabriele, B.; Salerno, G. PdI2. In e-EROS (Electronic Encyclopedia of Reagents for Organic
Synthesis); Crich, D., Ed.; Wiley-Interscience: New York, 2006. (b) Gabriele, B.; Salerno, G. Costa, M. Top.
Organomet. Chem. 2006, 18, 239-272. (c) Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli, G. P. Curr. Org.
Chem. 2004, 8, 919-946. (d) Gabriele, B.; Salerno, G.; Costa, M. Synlett 2004, 2468-2483. (e) Gabriele, B.;
Salerno, G.; Costa, M.; Chiusoli, G. P. J. Organomet. Chem. 2003, 687, 219-228.
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(10) For an interesting review on iodide effects in transition metal catalyzed reactions, including
carbonylations, see: Maitlis, P. M.; Haynes, A.; James, B. R.; Catellani, M.; Chiusoli, G. P. Dalton Trans. 2004,
3409-3419.
(11) See, for example, Yin, X.; Moss, J. R. Coord. Chem. Rev. 1999, 181, 27-59 and references therein.
(12) Procedure adapted from (a) Zhivotova, T. S.; Gazaliev, A. M.; Fazylov, S. D.; Aitpaeva, Z. K.;
Turdybekov, D. M. Russ. J. Org. Chem. 2006, 42, 448-450. See also: (b) Veltri, L.; Grasso, G.; Rizzi, R.;
Mancuso, R.; Gabriele, B. Asian J. Org. Chem. 2016, 5, 560-567.
(13) Perrin, L.; Hudhomme, P. Eur. J. Org. Chem. 2011, 28, 5427 – 5440.
(14) Procedure adapted from: Barbosa, F. C. G.; de Oliveira, R. N. J. Braz. Chem. Soc. 2011, 22, 592-597.
See also reference 12b.
(15) Yaroshenko, T. I.; Nakhmanovich, A. S.; Larina, L. I.; Elokhina, V. N.; Amosova, S. V. Chem.
Heterocycl. Compds. 2008, 44, 1129-1134.
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