Synthesis of some 4-oxothiochromenes and related compounds

Article abstract of DOI:10.1071/CH05205

Thiosalicylic acids react with 2-substituted N,N-dialkyl acetamides to give 3-substituted-N,N-dialkyl-2-amino-4-oxothiochromenes 13. N-Alkyl 2-piperidone and analogous caprolactams give derivatives of 1,2,3,4-tetrahydrothiochromeno[2, 3-b]pyridin-5-one 16

Full text of DOI:10.1071/CH05205

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2005, 58, 864–869
www.publish.csiro.au/journals/ajc
Synthesis of Some 4-Oxothiochromenes and Related Compounds
Andris J. Liepa,A,B Oanh Nguyen,A and Simon SaubernA
A CSIRO Molecular and Health Technologies, Clayton South VIC 3169, Australia.
B Corresponding author. Email: andy.liepa@csiro.au
Thiosalicylic acids react with 2-substituted N,N-dialkyl acetamides to give 3-substituted-N,N-dialkyl-
2-amino-4-oxothiochromenes 13. N-Alkyl 2-piperidone and analogous caprolactams give derivatives of
1,2,3,4-tetrahydrothiochromeno[2,3-b]pyridin-5-one16a–16dand7,8,9,10-tetrahydro-6H-5-thia-6-aza-cyclohepta-
[b]-naphthalen-11-one 16e, 16f. 2-Mercaptonicotinic acid gave a 1,2,3,4-tetrahydro-9-thia-1,8-diazaanthracen-10-
one 16g and a 1,2,3,4-tetrahydro-9-thia-1,8-diazaanthracene-10-thione 16h.
Manuscript received: 5 August 2005.
Final version: 25 October 2005.
Introduction
reaction with phosphorus oxychloride to form electrophilic
iminium halides. Among the numerous applications for such
active intermediates is the conversion of a cyanoacetamide
(1, Scheme 1) into an amidine 3.[4]
The search for useful biological activity relies upon a con-
tinuing supply of novel molecules, especially those with
moderate molecular weight and specific properties.[1] Pro-
viding a stream of synthetic molecules that are novel yet
readily accessible presents a formidable ongoing challenge
in synthetic chemistry. Time and cost place constraints on
the selection of eligible starting materials. Conversely, there
is a continuing need for innovative synthesis strategies with
which to provide access to uncommon structural domains.
In this context, thiochromones are of potential interest since
they manifest various forms of biological activity.[2]
Among such thiochromones, those bearing an amino
substituent in the 2-position are relatively rare. The few
known representatives have most commonly been prepared
by reaction of a 2-bromothiochroman with an amine.[3]
In order to increase product diversity within this domain,
it is beneficial to investigate a synthesis pathway alterna-
tive to those already described in the chemical literature.
Preferably, this route would enable a nitrogen-containing sub-
stituent to be incorporated at an early stage in the synthesis,
such as during assembly of the thiochroman ring. Retrosyn-
thetic analyses suggest that amides are prominent among the
alternative amine-related compounds for prospective start-
ing materials. This compound class is readily available, is
diverse and is amenable to chemical activation. For example,
it is well known that many tertiary amides can be activated by
It is possible that p-toluidine can react with a mild carbon-
centred electrophile (iminium halide, a probable interme-
diate, 2 Scheme 1) even in the presence of a strongly
electrophilic phosphorus-centred reagent (phosphorus oxy-
chloride). Further, cyanoacetamides contain an activated
methylene group that is potentially susceptible to elec-
trophilic attack. It was realized that the presence of such
potential for both electrophilic and nucleophilic reactivity
might be exploited to provide a simple one-step synthesis of
the desired 2-aminothiochromans.
Mercapto groups are powerful nucleophiles that retain
some nucleophilicity within the strongly acidic/electrophilic
environment in the presence of phosphorus oxychloride. In
the presence of a suitably located carboxylic acid group, a
thiochromene could result from the initial tethering of a mer-
captan to the iminium chloride of 4 (Scheme 2) followed by
acylation of the activated methylene group.The required con-
figuration of reactive groups is evident within thiosalicylic
acid 5 (Scheme 2).
Results and Discussion
In order to broaden the scope of the proposed synthesis
the supply of substituted thiosalicylic acids was diversified.
Me
Ϫ
O
Me
Cl
Cl
ϩ
N
N
NC
NC
POCl3
N
ϩ
NC
N
NH2
3
1
2
Scheme 1.
© CSIRO 2005
10.1071/CH05205
0004-9425/05/120864

4-Oxothiochromenes and Related Compounds
865
R1
N
SH
O
S
O
POCl3
R2
ϩ
NC
R1
OH
N
CN
R2
O
4
5
6
Scheme 2.
S
NMe2
O
NMe2
Me
Me
Me
Me
Cl
NMe2
OH
O
S
SH
S
220ЊC
NaOH
NaH/DMF
CO2Me
CO2Me
CO2Me
CO2H
7
8
9
10
Scheme 3.
Such compounds have been prepared[5] by diazotization of
substituted anthranilic acids followed by displacement of
nitrogen with a suitable sulfur nucleophile. Alternatively, a
method[6] has been developed for converting phenols into
the corresponding mercaptans based upon a thermal rear-
rangement of an N,N-dimethyl thiocarbamate. Since a variety
of salicylic acids is readily available, an investigation of the
applicability of this methodology to the conversion of sali-
cylic acids into their thio analogues was of interest. Treating
N,N-dimethylthiocarbamoyl chloride with the sodium salt of
methyl 2-hydroxy-3-methylbenzoate 7 (Scheme 3) in N,N-
dimethylformamide at 80◦C gave the corresponding crude
thiocarbamate 8 (Scheme 3) in 59% yield.
Table 1. Preparation of 2-amino-4-oxo-4H-thiochromenes
R1
SH
S
N
O
POCl3
R2
ϩ
R
R1
OH
N
R
R3
R3
R2
O
O
11
12
13
R
R1
R2 R3
R3
Yield [%]
11
11
11 12
13
a
b
c
d
e
f
g
h
i
CN
CN
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)5-
-(CH2)5-
H
H
44
36
64
63
66
32
5-Cl 6-Cl
4-Cl 7-Cl
3-Me 8-Me
CO2Me
CO2Et
CO2Me
CO2Et
Cl
Cl
SO2Ph
SO2Ph(4-Me) Et
H
H
Heating the thiocarbamate 8 (Scheme 3) in triethylenegly-
col dimethyl ether (triglyme) at the boiling point for 24 h then
gave a moderate yield of the rearranged material 9 (Scheme 3)
(53% of crude product). Although a longer period at reflux
consumed more of the starting material, this process also
led to an increase in by-products. The technique of heating
by microwave may benefit reactions requiring high tempera-
ture by decreasing the time required, as well as diminishing
by-product formation. It was found that when methyl 2-N,N-
dimethylcarbamoyloxy-3-methyl benzoate 8 was heated in
triglyme in a microwave oven at 250◦C for 60 min a 79% yield
4-Cl 7-Cl
-CH2C(Me)2(CH2)3-
Et Et
-CH2C(Me)2(CH2)3-
Et
—
—
H
—
—
H
55
53
j
H
H
13a and 13b (Table 1) while simultaneously establishing a
cyano substituent in the 3-position.
It was evident that activation of the methylene group
in 11, presumably a requirement to enable condensation
to occur, might also be affected by electron-withdrawing
substituents other than nitrile in the 2-position of the N,N-
dialkylacetamide precursors 11. Such a modification would
also provide opportunities for variation of the substituent in
the 3-position of the resulting thiochromenes 13. In order to
evaluate the ability of an ester moiety to achieve such acti-
vation in place of a nitrile, a series of malonamides 11c–11f
(Table 1) was prepared by transamination of malonic esters
with either pyrrolidine or piperidine. These precursors also
condensed readily with thiosalicylic acids 12 to form the
corresponding thiochromene esters 13c–13f. Aryl sulfonyl
substituents could also be introduced into the 3-position with-
out difficulty. Thus, treatment of chloroacetamides 11g and
11h (Table 1) with sodium benzene or sodium p-toluene sul-
finate, respectively, gave the 2-arylsulfonyl acetamides 11i
and 11j. These compounds also condensed with thiosalicylic
1
of 9 (estimated by H NMR spectroscopy) was obtained.
Hydrolysis then gave thiosalicylic acid 10.
Thiosalicylic acid reacted readily with the cyanoacetamide
11a in refluxing 1,2-dichloroethane in the presence of
excess of phosphorus oxychloride, to form 2-pyrrolidino-
4-oxo-4H-thiochromene 13a (Table 1) in 44% yield. A
described previously,[7] pyridine 6-chloro-2,4-dipyrrolidin-
1-ylnicotinonitrile was also obtained in 46% yield because
of self-condensation of the cyanoacetamide 11a.
Although 1,2-dichloroethane was chosen as solvent for
the initial condensation, it was later found that acetonitrile
gave better results, and most of the subsequent reactions
were carried out in this medium. Under these conditions self-
condensation of the cyanoacetamide 11a was not observed.
This new condensation protocol (Table 1) was useful in pro-
viding modest yields of the 2-dialkylaminothiochromenes

866
A. J. Liepa, O. Nguyen, and S. Saubern
Table 2. Preparation of tricyclic thiochromenes
Experimental
R1
N
R1
N
Materials and Methods
S
X
O
SH
X
Light petroleum is the 40–60◦C-bp fraction. Unless specified, 1H and
13C NMR spectra were recorded on a Bruker Av400 spectrometer at
400 MHz and 100.6 MHz, respectively, using CDCl3 solutions. Chemi-
cal shifts are measured in ppm. Mass spectra were recorded on a Fisons
Instruments VG Platform quadrupole using either atmospheric pres-
sure chemical ionization (APCI) or electrospray ionization (ESI) in
the positive- and/or negative-ion mode with a cone voltage of 30 eV
for both APCI and ESI, using either 1/1 acetonitrile/water or methanol
as solvent. Microanalyses were performed by the Campbell Microana-
lytical Laboratory, University of Otago. Melting points were recorded
on a Reichert-Kofler hot-stage micro-melting point apparatus, and are
uncorrected. FlashcolumnchromatographywascarriedoutusingMerck
Kieselgel 60 (230–400 mesh; particle size 0.04–0.63 mm) silica gel.
Radial chromatography was performed with silica gel (60 PF254) coated
glass rotors by means of a Harrison Research Chromatotron (Model
7924T). Analytical thin-layer chromatography (TLC) was conducted on
Sigma–Aldrich silica gel on polyester sheets with ultraviolet indicator.
Microwave heating was carried out in a BIOTAGE ‘Initiator’ 60.
POCl3
ϩ
OH
n
n
R3
R3
Y
O
14
15
16
R1
14
n
X
Y
R3
Yield [%]
15, 16
a
b
c
d
e
f
Me
Pr
1
1
1
1
2
2
1
1
CH
CH
CH
CH
CH
CH
N
O
O
O
O
O
O
O
S
H, H
H, H
4-Cl, 8-Cl
4-Cl, 8-Cl
H, H
H, H
H, H
H, H
37
69
21
26
28
15
29
14
Et
(2-Cl)PhCH2
Me
(4-Cl)PhCH2
PhCH2
g
h
PhCH2
N
Methyl 3-Oxo-3-pyrrolidin-1-yl-propionate 11c and
Methyl 3-Oxo-3-piperidin-1-yl-propionate 11e
acid to give the corresponding 3-arysulfonyl thiochromenes
13i and 13j.
A mixture of dimethyl malonate (1 mol), benzene (200 mL), and the
amine (1.1 mol) was stirred for 2 h then refluxed for 48 h. The easily
volatilized components were removed using a rotary evaporator, and
the respective residues were fractionally distilled to give the following.
Methyl 3-oxo-3-pyrrolidin-1-yl-propionate, bp 110–113◦C (0.2 mm,
62%). (Found: C 56.2, H 7.4, N 8.1. C8H13NO3 requires C 56.1, H 7.65,
N 8.2%). δH 1.85 (4H, m, NCH2CH2CH2), 3.33 (2H, s, COCH2), 3.42
(4H, m, CH2NCH2), 3.66 (3H, s, CH3). Methyl 3-oxo-3-piperidin-1-
yl-propionate, 109–112◦C (0.5 mm, 73% yield). (Found: C 58.2, H 8.1,
N 7.4%. C9H15NO3 requires C 58.4, H 8.2, N 7.6%). δH 1.58 (6H, m,
NCH2CH2CH2CH2), 3.34 (2H, m, NCH2), 3.43 (2H, s, COCH2), 3.58
(2H, m, CH2N), 3.73 (3H, s, CH3).
With variations in the substituent at the 3-position demon-
strated, the effect of varying substituents in the thiosalicylic
acid moiety upon the cyclization was briefly examined.These
condensations proceeded as expected. The presence of a
methyl group adjacent to the mercapto group in the thio-
salicylic acid 10 (Scheme 3) did not prevent cyclization to
form 13d.
The device of using activation by an iminium salt to enable
acylation of an adjacent carbon also offered an opportu-
nity to generate tricyclic thiochromene analogues. Thus, if
an N-alkylated lactam was the starting material, the initially
formed iminium salt should react with the mercapto group
of a thiosalicylic acid. This process would give an inter-
mediate that could be sufficiently activated to undergo an
intramolecular acylation leading to formation of an addi-
tional ring. Such a condensation proceeded without difficulty,
albeit slowly, in dichloromethane, and this allowed several N-
alkylated piperidine 2-ones(14a–14d, 14g)and caprolactams
(14e and 14f) to be converted into the corresponding tri-
cyclic products (Table 2). However, attempts to similarly use
N-alkylated pyrrolidin-2-ones did not produce tricyclic
material that could be isolated when treated with either
thiosalicylic acid or 2-mercaptonicotinic acid. When a reac-
tion was carried out between 1-benzyl-2-piperidone and
2-mercaptonicotinic acid 15 (X = N, R3 = H) in sulfolane,
a small amount (14%) of the thione analogue 16h of the
anticipated product 16g was obtained with only a trace of
16g being formed. This product selectivity was reversed
when 1-benzyl-2-piperidone was first reacted overnight with
an excess of phosphorus oxychloride and then treated with
2-mercaptonicotinicacid. Undertheseconditionsa29%yield
of 16g was isolated and a very small amount of the thione
16h was observed. The reactions that produce the thione 16h
have not been investigated, but thione may result from for-
mation of an imidoyl chloride from the vinylogous amide
16g, followed by reaction with 2-mercaptonicotinic acid and
subsequent cleavage of the pyridine–sulfur bond.
2-Mercapto-3-methylbenzoic Acid 10 from
2-Dimethylthiocarbamoyloxy-3-methylbenzoate 8
Sodium hydride (150 mg, 50% in oil) was added to a solution of
methyl 2-hydroxy-3-methyl benzoate (500 mg, 3.0 mmol) in N,N-
dimethylformamide (15 mL).The suspension was heated to 80◦C before
adding dimethylthiocarbamoyl chloride (450 mg, 3.6 mmol). The reac-
tionmixturewasheatedfor2 hat80◦Cthencooledonice.Water(60 mL)
was added and the solution extracted with ethyl acetate (2 × 30 mL).
The combined extracts were washed with brine (2 × 30 mL), dried
(MgSO4), and concentrated to form a yellow oil. Flash chromatogra-
phy using ethyl acetate/petroleum spirits (1/1) as eluent provided methyl
2-dimethylthiocarbamoyloxy-3-methylbenzoate 8 (450 mg, 59%) as an
oil that solidified on standing. Recrystallization (light petroleum) gave
a pale tan solid, mp 103–104◦C (Found: C 56.6, H 6.0, N 5.75, S 12.5.
C12H15NO3S requires C 56.9, H 6.0, N 5.5, S 12.7%). δH 2.25 (3H, s,
3-Me), 3.48, 3.41 (3H each, each s, NMe2), 3.83 (3H, s, CO2Me), 7.21
(1H, t, J 7.7, H5), 7.43 (1H, dd, J 7.7, 1.8, H4), 7.85 (1H, dd, J 7.7 and 1.8,
H6). The thiocarbamate 8 (470 mg) was dissolved in triethyleneglycol
dimethylether(10 mL), thesolutionwasdegassed, placedinapre-heated
oil bath (220◦C), and stirred under nitrogen until TLC analysis (1/1
light petroleum/ethyl acetate) confirmed the starting material was fully
rearranged (typically 24 h). The reaction was cooled to room tempera-
ture, diluted with water (80 mL) and extracted with toluene (3 × 30 mL).
The combined extracts were washed with brine (3 × 50 mL) and con-
centrated. Flash chromatography using ethyl acetate/light petroleum
(1/1) as eluent provided crude methyl (2-dimethylcarbamoylsulfanyl-
3-methyl) benzoate 9 (240 mg, 53%) as an oil. δH 2.44 (3H, s, 3-Me),
3.09 (6H, br s, NMe2), 3.84 (3H, s, CO2Me), 7.31 (1H, t, J 7.7, H5), 7.43
(1H, dd, J 1.8, 7.7, H4), 7.56 (1H, dd, J 1.8, 7.7, H6). The oil was dis-
solved in a mixture of methanol (5 mL) and aqueous sodium hydroxide
(2.5 equiv. NaOH, 1 mL) then the solution was heated at reflux for 8 h
under nitrogen. The reaction was cooled to room temperature, diluted

4-Oxothiochromenes and Related Compounds
867
with water (20 mL), and washed with dichloromethane (3 × 10 mL).
The aqueous phase was acidified to pH 1 with concentrated hydrochlo-
ric acid then extracted with ethyl acetate (3 × 10 mL). The combined
extracts were dried (MgSO4) and concentrated giving 2-mercapto-3-
methylbenzoic acid (90 mg, 56%) as a white powder, mp 157–159◦C
(lit.[8] 155–157◦C). δH 2.40 (3H, s, 3-Me), 6.54 (1H, s, SH), 7.09 (1H,
t, J 7.5, H5), 7.36 (1H, d, J 7.5, H4), 8.04 (1H, d, J 7.5, H6).
temperature and quenched with saturated aqueous sodium bicarbon-
ate (2 mL). The reaction was extracted with ethyl acetate (3 × 5 mL),
and the combined extracts were filtered through a small plug of silica
gel. The filtrate was concentrated to afford an orange solid (430 mg,
64%) that was recrystallized from ethanol to give the product 13c as
granular orange crystals, mp 225–227◦C. (Found: C 55.8, H 4.4, N 4.5,
S 9.8. C15H14ClNO3S requires C 55.6, H 4.4, N 4.3, S 9.9%). δH 1.99
(4H, m, NCH2CH2CH2), 3.49 (4H, m, CH2NCH2), 3.89 (3H, s, Me),
7.32–7.37 (3H, m, 2ArH), 8.31 (1H, d, J 9.1, ArH). δC 25.4, 50.6, 52.6,
107.4, 124.0, 127.5, 128.0, 129.8, 133.6, 137.0, 155.4, 169.3, 176.6.
m/z (APCI) 324.1, 326.1 [M + H]+.
Preparation of 5-Chloro-2-mercaptobenzoic Acid
A solution of methyl 5-chloro-2-hydroxybenzoate (5.0 g) in N,N-
dimethylformamide (20 mL) was treated with excess sodium hydride
(1.3 g, 50% in oil). The suspension was heated to 80◦C before adding
N,N-dimethylthiocarbamoyl chloride (5.0 g, 1.5 equiv.). Heating of the
reaction mixture was continued for 2 h before cooling on ice. The reac-
tion mixture was diluted with water (50 mL), then extracted into toluene
(3 × 50 mL). The combined extracts were concentrated to form a vis-
cous orange oil. The oil was diluted with triethyleneglycol dimethyl
ether (50 mL), the solution was degassed, the reaction mixture was then
placed in a pre-heated sand bath and heated to a gentle reflux for 4 h
under nitrogen. The solution was cooled, treated with aqueous sodium
hydroxide(2.5 M, 30 mL), andstirredatroomtemperaturefor16 hunder
nitrogen. The reaction mixture was cooled to 0–5◦C, and acidified to
pH 1 with concentrated hydrochloric acid to form an off-white precip-
itate. The solid was filtered off, washed with water, and dried to afford
5-chloro-2-mercaptobenzoic acid (3.95 g, 78% overall). δH 7.28 (1H, d,
J 8.3, H3), 7.35 (1H, dd, J 8.3 and 2.2, H4), 8.11 (1H, d, J 2.2, H6). mp
192–194◦C (lit.[9] 193–194◦C).
Ethyl 8-Methyl-4-oxo-2-pyrrolidin-1-yl-4H-thiochromene-
3-carboxylate 13d
A mixture of 3-methyl-2-mercaptobenzoic acid (90 mg, 0.54 mmol)
and ethyl 3-oxo-3-pyrrolidin-1-yl-propionate (100 mg, 0.540 mmol) in
acetonitrile (5 mL) was heated to 60◦C and treated with phosphorus oxy-
chloride (100 µL, 1.1 mmol) to afford a yellow solid (107 mg, 63%), mp
189–192◦C. Recrystallization from ethyl acetate gave the product 13d
as yellow crystals, mp 202–204◦C. (Found: C 64.2, H 6.2, N 4.5, S 9.9.
C17H19NO3S requires C 64.3, H 6.0, N 4.4, S 10.1%). δH 1.41 (3H,
t, J 7.2, CO2CH2CH3), 1.98–2.08 (4H, m, 2-NCH2CH2), 2.44 (3H, s,
8-Me), 3.55–3.65 (4H, m, 2-NCH2), 4.40 (2H, q, J 7.2, CO2CH2CH3),
7.35–7.33 (2H, m, H5 and H7), 8.33 (1H, m, H6). δC 14.0, 18.9, 25.4,
50.5, 61.5, 107.4, 126.0, 126.1, 129.6, 131.3, 131.9, 132.9, 154.6, 169.1,
177.7.
Methyl 4-Oxo-2-piperidin-1-yl-4H-thiochromene-3-carboxylate 13e
4-Oxo-2-pyrrolidin-1-yl-4H-thiochromene-3-carbonitrile 13a
Phosphorus oxychloride (1.17 mL, 12.5 mmol) was added to a stirred
suspension of 2-mercaptobenzoic acid (0.77 g, 5.0 mmol) and methyl
3-oxo-3-piperidin-1-yl-propionate (1.0 g, 6.0 mmol) in acetonitrile
(10 mL). The mixture was stirred at room temperature for 10 min, then
heated at 70◦C for 2 h. The yellow suspension, which formed a homoge-
nousdarkredsolutionduringheating, wasthencooled, pouredintowater
(10 mL), and neutralized with solid potassium carbonate (1–2 g). After
5 min, the solids were collected, washed with water then ether to give
the crude thiochromene (1.0 g, 66%) as an orange solid, mp 143–146◦C.
A portion was recrystallized from ethyl acetate after passing it through
a plug of silica to give 13e as orange crystals, mp 145–146◦C. (Found:
C 63.5, H 5.8, N 4.8, S 10.6. C16H17NO3S requires C 63.3, H 5.7,
N 4.6, S 10.6%). νmax (KBr)/cm−1 1724 (CO2Me). δH 1.69 (6H, m,
piperidine H), 3.46 (4H, m, piperidine H), 3.91 (3H, s, Me) 7.40–7.56
(3H, m, 3ArH), 8.40 (1H, dd, J 1.1, 8.41,ArH). δC 23.8, 25.7, 52.3, 52.6,
113.1, 125.3, 127.2, 128.6, 130.0, 131.2, 132.5, 161.9, 168.4, 178.2. m/z
(APCI) 304 [M + H]+.
A mixture of 2-mercaptobenzoic acid (0.51 g, 3.3 mmol), phosphorus
oxychloride (1.0 g, 6.6 mmol) and 3-oxo-3-pyrrolidin-1-yl-propionitrile
(0.46 g, 3.3 mmol) in 1,2-dichloroethane (12 mL) was heated at reflux
for 4 h. The solution was cooled, stirred with water (30 mL) for 4 h, and
adjusted to pH 9 by portion-wise addition of solid potassium carbon-
ate. The material obtained after evaporation of the organic layer was
chromatographed over silica gel with elution by dichloromethane fol-
lowed by 10% ethyl acetate in dichloromethane to afford two major
products. The first was 6-chloro-2,4-dipyrrolidin-1-yl-nicotinonitrile
(105 mg, 46%),[7] mp 128–130◦C (lit. 129–131◦C). δH 1.8–2.2 (8H,
m, pyrrolidine H), 3.4–3.8 (8H, m, pyrrolidine H), 6.00 (s, 1H, pyridine
H). δC 25.5(4 × CH2, overlapping), 49.8(2 × NCH2), 50.3(2 × NCH2),
72.6, 96.9, 119.0, 152.7, 158.3, 160.4. Evaporation of the later fractions
gaveapaleyellowsolidthatwasrecrystallizedfromacetonitriletoafford
the product 13a as white fluffy needles (0.37 g, 44%), mp 236–237◦C.
(Found: C 65.5, H 4.7, N 11.1, S 12.4. C14H12N2OS requires C 65.6,
H 4.7, N 10.9, S 12.5%). νmax (KBr)/cm−1 2204 (CN). δH 2.10 (4H, m,
NCH2CH2CH2), 3.89 (4H, m, CH2NCH2), 7.30–7.51 (3H, m, 3ArH),
8.42 (1H, dd, J 1.8, 9.5, ArH). δC 25.5 (CH2CH2N), 52.5 (CH2N), 85.3
(C3), 118.0 (CN), 125.0 (C8), 127.6 (C7), 128.3 (C8a), 128.5 (C5),
130.9 (C4a), 131.7 (C6), 162.4 (C2), 178.3 (C4). m/z (APCI) 257.2
[M + H]+.
Ethyl 7-Chloro-4-oxo-2-piperidin-1-yl-4H-thiochromene-
3-carboxylate 13f
Similarly, 13f was prepared from 4-chloro-2-mercaptobenzoic acid,
phosphorus oxychloride, and 3-oxo-3-piperidin-1-yl-propionic acid
ethyl ester in acetonitrile yielding 13f (32%) as an orange oil after
chromatography over silica gel. (Found: C 57.8, H 5.4, N 4.1, S 8.9.
C17H18ClNO3SrequiresC58.0, H5.2, N4.0, S9.1%). νmax (neat)/cm−1
1720 (CO2Et). δH 1.38 (3H, t, J 7.3, CH2CH3), 1.67 (6H, m, piperidine
H), 3.46 (4H, m, piperidine H), 4.36 (2H, q, J 7.3, CH2CH3), 7.40 (2H,
m, 2ArH), 8.31 (1H, d, J 9.1, ArH). δC 14.2, 23.8, 25.7, 52.4, 61.7,
113.6, 124.6, 127.8, 128.4, 130.2, 134.1, 137.6, 161.2, 167.6, 177.4.
m/z (APCI) 352.2, 354.2 [M + H]+.
6-Chloro-4-oxo-2-pyrrolidin-1-yl-4H-thiochromene-3-carbonitrile 13b
This product was prepared in an analogous manner to 13a and recrys-
tallized from chloroform/ethanol to give the product 13b as pale yellow
shiny crystals (36%), mp 281–282◦C. (Found: C 57.7, H 3.6, N 9.7,
S 10.9. C14H11ClN2OS requires C 57.8, H 3.8, Cl 12.2, N 9.6, S 11.0%).
νmax (KBr)/cm−1 2195. δH 2.14 (4H, m, 4cycpentH), 3.92 (4H, m,
4cycpentH), 7.30 (1H, d, J 8.8,ArH), 7.45 (1H, dd, J 2.2, 8.8,ArH), 8.30
(1H, d, J 2.2, ArH). δC (125 Mz) 25.6, 53.5, 84.9 118.0, 126.7, 128.5,
128.7, 129.3, 133, 135, 163.8, 178.9. m/z (APCI) 291.2 [M + H]+.
2-Benzenesulfonyl-1-(3,3-dimethylpiperidin-1-yl)ethanone 11i
Twoequivalentsof3,3-dimethylpiperidineweretreatedwithchloroacetyl
chloride in ether at 0◦C followed by a wash with water and evaporation
of the solvent to give the crude chloroacetamide as an oil. δH (rotamer
mixture, 1:1) 0.87, 0.89 (6H, s, 2 × Me), 1.55, 1.64 (4H, m, piperidine
H), 3.07, 3.20(2H, s, NCH2CMe2), 3.37, 3.47(2H, m, NCH2CH2), 4.04,
4.07 (2H, s, ClCH2). The crude product was used without purification
in the following preparation.
Methyl 7-Chloro-4-oxo-2-pyrrolidin-1-yl-4H-thiochromene-
3-carboxylate 13c
A mixture of 4-chloro-2-mercaptobenzoic acid[9] (381 mg, 2 mmol) and
ethyl 3-oxo-3-pyrrolidin-1-yl-propionate (370 mg, 2 mmol) in acetoni-
trile (5 mL) was heated to 60◦C and treated with phosphorus oxychloride
(610 mg, 4 mmol). The reaction was stirred for 3 h, cooled to room

868
A. J. Liepa, O. Nguyen, and S. Saubern
Reaction of the crude chloroacetamide with sodium benzenesulfi-
CH2CH2CH2N), 7.45 (3H, m, 3 ×ArH), 8.54 (1H, m, ArH), δC 20.8
(C3), 21.6 (C4), 39.5 (C2), 52.2 (NCH3), 107.7 (C8), 125.1 (C9), 126.7
(C8), 128.4 (C6), 129.4 (C9a), 129.6 (C7), 131.5 (C5a), 155.1 (C10a),
176.2 (C5). m/z (APCI) 232.1 [M + H]+.
nate in aqueous N,N-dimethylformamide as for compound 11j below
gave the product 11i (73%) as colourless needles from aqueous ethanol,
mp 96–98◦C. (Found: C 60.8, H 7.3, N 4.5. C15H21NO3S requires C
61.0, H 7.2, N 4.7%). δH (rotamer mixture) 0.92, 0.94 (6H, s, 2Me),
1.22, 1.43, 1.78 (4H, m, piperidine H), 3.21, 3.25 (2H, s, NCH2CMe2),
3.51 (2H, m, NCH2CH2), 4.22, 4.39 (2H, s, COCH2), 7.56 (2H, m,
2 ×ArH), 7.66 (1H, m, ArH), 7.93 (2H, m, ArH).
1-Propyl-1,2,3,4-tetrahydrothiochromeno[2,3-b]pyridin-5-one 16b
The reaction between N-propyl-2-piperidone (0.5 g, 3.5 mmol), phos-
phorus oxychloride (0.83 mL, 8.90 mmol), and 2-mercaptobenzoic acid
(0.61 g, 4.0 mmol) gave the crude thiochromene which was purified by
radial chromatography over silica (ethyl acetate/light petroleum, 1/9)
to give a yellow solid (0.63 g, 69%), mp 106–108◦C. Recrystallization
from benzene/cyclohexane gave pale yellow needles, mp 107–108◦C.
(Found: C 69.5, H 6.7, N 5.5, S 12.1. C15H17NOS requires C 69.5, H 6.6,
N 5.4, S 12.4%). δH 0.96 (3H, t, J 7.3, Me), 1.67 (4H, m), 1.91 (4H,
m), 2.75 (2H, m), 3.37 (3H, m), 7.38 (3H, m, 3ArH), 8.41 (H, m, ArH).
δC 11.2, 20.7, 20.9, 22.1, 50.3, 54.2, 107.5, 125.2, 126.7, 128.4, 129.5,
129.7, 131.5, 154.2, 176.8. m/z (APCI) 260.3 [M + H]+.
3-Benzenesulfonyl-2-(3,3-dimethylpiperidin-1-yl)thiochromen-
4-one 13i
In a manner similar to 13c, 13i was prepared from 2-mercaptobenzoic
acid (0.5 g, 3.4 mmol), phosphorus oxychloride (1.1 g, 7.2 mmol),
and 2-benzenesulfonyl-1-(3,3-dimethylpiperidin-1-yl)ethanone (1 g,
3.4 mmol). Recrystallization from ethanol gave the product 13i as white
granular crystals (0.76 g, 55%), mp 259–260◦C. (Found: C 63.9, H 5.8,
N 3.6, S 15.6. C22H23NO3S2 requires C 63.9, H 5.6, N 3.4, S 15.5%).
δH 0.99 (6H, s, 2Me), 1.53 (2H, m, piperidine H), 1.85 (2H, m, piperi-
dine H), 3.61, 3.87 (each 2H, each m, CH2NCH2), 7.28–7.46 (6H, m,
6 ×ArH), 7.90 (2H, dd, 7.7, 8.4, 2 ×ArH), 8.02 (1H, dd, J 1.1, 9.1,ArH).
δC 21.8, 22.6, 33.5, 37.0, 55.6, 67.1, 112.7, 125.4, 127.4, 127.7, 128.0,
128.4, 130.7, 131.1, 131.9, 132.0, 143.8, 165.0, 177.5. m/z (APCI) 414.2
[M + H]+.
8-Chloro-1-ethyl-1,2,3,4-tetrahydrothiochromeno[2,3-b]pyridin-
5-one 16c
In a similar manner to 16b, 16c was prepared using 4-chloro-2-
mercaptobenzoic acid (0.82 g, 4.3 mmol), phosphorus oxychloride
(0.92 mL, 9.8 mmol), and N-ethyl-2-piperidone (0.5 g, 3.9 mmol). The
product 16c was obtained (0.23 g, 21%) as yellow prisms after recrys-
tallization from ethyl acetate, mp 177–179◦C. (Found: C 59.9, H 5.0,
N 5.1, S 11.3. C14H14ClNOS requires C 60.1, H 5.0, Cl 12.7, N 5.0,
S 11.5%). δH 1.26 (3H, t, J 6.9, Me), 1.93 (2H, m, CH2CH2CH2), 2.73
(2H, m, NCH2CH2CH2), 3.36 (2H, m, NCH2CH2CH2), 3.50 (q, J 6.9,
CH2Me), 7.32 (2H, m, 2 ×ArH), 8.34 (1H, d, J 8.8,ArH). δC 12.2, 20.7,
21.9, 47.3, 49.6, 107.6, 124.4, 127.3, 127.7, 130.0, 132.8, 135.9, 153.7,
175.5. m/z (APCI) 280.1, 282.1 [M + H]+.
N,N-Diethyl-2-(toluene-4-sulfonyl)acetamide 11j
A mixture of 2-chloro-N,N-diethylacetamide (3.0 g, 20 mmol) and
hydrated sodium p-toluenesulfinate (5.0 g) in a mixture of N,N-
dimethylformamide (20 mL) and water (5 mL) was stirred at 50◦C for
16 h, diluted with water (100 mL), and stirred at room temperature until
the precipitated oil had solidified. The solid was collected by filtration
and recrystallized from cyclohexane to give the product 11j as white
granular crystals (3.6 g, 67%), mp 85–86◦C. (Found: C 57.8, H 7.4,
N 5.3. C13H19NO3S requires C 58.0, H 7.1, N 5.2%). δH 1.04 (3H, t, J
7.3, NCH2CH3), 1.15 (3H, t, J 7.3, NCH2CH3), 2.38 (3H, s, ArCH3),
3.27 (2H, q, J 7.3, NCH2), 3.40 (2H, q, J 7.3, NCH2), 4.15 (2H, s,
COCH2), 7.28 (2H, d, J 8.0, 2 ×ArH), 7.72 (2H, d, J 8.4, 2 ×ArH). δC
12.7, 14.2, 21.7, 40.7, 43.1, 59.8, 128.6, 129.6, 135.8, 145.1, 160.5. m/z
(APCI) 270.3 [M + H]+.
8-Chloro-1-(2-chlorobenzyl)-1,2,3,4-tetrahydrothiochromeno-
[2,3-b]pyridin-5-one 16d
This compound was prepared similarly from 4-chloro-2-
mercaptobenzoic acid (0.5 g, 2.6 mmol), phosphorus oxychloride
(0.62 mL, 6.6 mmol), and 1-(2-chloro-benzyl)piperidin-2-one (0.6 g,
2.64 mmol). The product (0.26 g, 26%) formed yellow needles after
recrystallization from ethyl acetate, mp 197–199◦C. (Found: C 60.4,
H 4.0, N 3.7, S 8.5. C19H15Cl2NOS requires C 60.6, H 4.0, Cl
18.8, N 3.7, S 8.5%). δH 2.04 (2H, m, CH2CH2CH2), 2.90 (2H, m,
CH2CH2CH2N), 3.47 (2H, m, J 5.8, CH2CH2CH2N), 4.81 (2H, s,
CH2Ph), 7.28–7.48 (m, 6 ×ArH), 8.43 (1H, d, J 9.1, ArH). δC 20.7,
22.0, 51.0, 53.9, 108.6, 124.6, 127.0, 127.2, 127.4, 127.7, 129.3, 130.1,
130.2, 132.3, 132.7, 133.2, 136.5, 155.3, 175.3. m/z (APCI) 375.9, 378.0
[M + H]+.
2-Diethylamino-3-(toluene-4-sulfonyl)thiochromen-4-one 13j
Phosphorus oxychloride, 2-mercaptobenzoic acid, and N,N-diethyl-2-
(toluene-4-sulfonyl)acetamide were reacted in acetonitrile to give 13j.
Recrystallization from aqueous ethanol gave the product as colourless
shiny crystals (53%), mp 180–181◦C. (Found: C 61.8, H 5.7, N 3.7,
S 16.3. C20H21NO3S2 requires C 62.0, H 5.5, N 3.6, S 16.6%). δH 1.38
(6H, t, J 7.3, 2NCH2CH3), 2.32 (3H, s, ArCH3), 3.91 (4H, q, J 7.3,
2NCH2), 7.12 (2H, d, J 8.0, 2ArH), 7.32–7.53 (3H, m, 3ArH), 7.74
(2H, d, J 8.4, 2ArH), 8.06 (1H, dd, J 1.5, 9.5, ArH). δC 13.3, 21.5, 50.1,
114.0, 125.3, 127.4, 127.9, 128.5, 128.6, 130.7, 131.5, 131.7, 140.7,
142.6, 164.9, 177.2. m/z (APCI) 388.2 [M + H]+.
1-Methyl-1,2,3,4-tetrahydrothiochromeno[2,3-b]pyridin-5-one 16e
Preparation by the standard method from 2-mercaptobenzoic acid,
N-methylcaprolactam, and phosphorus oxychloride followed by recrys-
tallization from cyclohexane gave 16e as colourless crystals (28%), mp
79–80◦C. (Found: C 68.3, H 6.2, N 5.7, S 13.1. C14H15NOS requires
C 68.5, H 6.2, N 5.7, S 13.1%). δH 1.82 (4H, m, CH2CH2CH2CH2), 2.94
(2H, m, CH2CH2CH2CH2N), 3.12 (3H, s, Me), 3.41 (2H, m, CH2N),
7.44 (3H, m, 3ArH), 8.45 (1H, m, ArH). δC 23.1, 26.0, 26.1, 40.5, 55.0,
56.7, 117.7, 125.4, 126.7, 128.7, 130.1, 132.9, 159.4, 179.6. m/z (APCI)
246.1 [M + H]+.
1-Methyl-1,2,3,4-tetrahydrothiochromeno[2,3-b]pyridin-5-one 16a
N-Methyl-2-piperidone (0.4 g, 3.5 mmol) in dichloromethane (2 mL)
was added dropwise to a solution of phosphorus oxychloride (0.83 mL,
8.9 mmol) in dichloromethane (2 mL) at 0◦C. The mixture was stirred
at 0◦C for 10 min, then at room temperature for 1 h. Then 2-
mercaptobenzoic acid (0.61 g, 4.0 mmol) was added in one portion to the
mixture and the resultant yellow suspension was stirred at room temper-
ature for 3 days. The reaction mixture was poured into water (10 mL)
and neutralized with solid potassium carbonate (1–2 g), followed by
extraction with dichloromethane. The organic phase was washed with
water, and concentrated under vacuum to form an oil phase that solid-
ified upon standing. The crude thiochromene was purified by radial
chromatography over silica (ethyl acetate/light petroleum, 1/9). Recrys-
tallization from ethyl acetate gave light yellow crystals (0.34 g, 37%),
mp 158–160◦C. (Found: C 67.3, H 5.8, N 6.1, S 14.0. C13H13NOS
requires C 67.5, H 5.7, N 6.1, S 13.9%). δH 1.99 (2H, m, CH2CH2CH2),
2.84 (2H, m, CH2CH2CH2N), 3.20 (3H, s, Me), 3.44 (2H, m,
6-(4-Chlorobenzyl)-7,8,9,10-tetrahydro-6H-5-thia-
6-azacyclohepta[b]naphthalen-11-one 16f
In a similar manner, 16f was prepared from 2-mercaptobenzoic acid
(0.4 g, 2.52 mmol), phosphorus oxychloride (0.5 mL, 5.3 mmol), and
N-(4-chlorobenzyl) caprolactam (0.5 g, 2.1 mmol). The crude prod-
uct (0.11 g, 15%) gave light-yellow oil after chromatography (ethyl
acetate/light petroleum, 1/9) that gradually solidified. Recrystalliza-
tion from cyclohexane gave 16f as a colourless solid, mp 228–230◦C.
(Found: C 67.4, H 5.0, Cl 10.1, N 3.8. C20H18ClNOS requires C 67.5,

4-Oxothiochromenes and Related Compounds
869
H 5.1, Cl 10.0, N 3.9%). δH 1.77 (4H, m, CH2CH2CH2CH2), 3.00 (2H,
m, CH2CH2CH2CH2N), 3.37 (2H, m, CH2CH2CH2CH2N), 4.62 (2H,
s, CH2Ph), 7.28–7.40 (4H, m, CH2Ph), 7.40–7.51 (3H, m, 3ArH), 8.47
(1H, m, ArH). δC 23.6, 26.5, 53.5, 56.6, 120.3, 125.8, 127.2, 129.1,
129.2, 129.3, 129.6, 130.0, 130.8, 133.4, 133.9, 135.8, 159.0, 180.7.
m/z (APCI) 356.1, 358.0 [M + H]+.
elution by dichloromethane. Combined yield of product 16h 0.45 g
(14%), mp 214–216◦C. (Found: C 66.5, H 5.0, N 8.6, S 19.6.
C18H16N2S2 requires C 66.6, H 5.0, N 8.6, S 19.8%). δH [(CD3)2SO],
2.48–2.51 (2H, m, CH2CH2CH2), 3.09 (2H, t, J 6.4, NCH2CH2CH2),
3.62–3.67 (2H, m, NCH2), 4.97 (2H, s, Ar CH2), 7.30–7.43 (5H, m,
ArH), 7.52–7.56 (1H, m, pyH), 8.61–8.63 (1H, m, pyH), 9.21–9.25
(1H, m, pyH). δC [(CD3)2SO] 20.5, 29.3, 51.7, 56.3, 122.2, 123.0,
126.7, 127.8, 129.0, 129.6, 134.5, 140.4, 148.6, 150.4, 156.4, 188.5.
m/z (APCI) 325.0 [M + H]+.
1-Benzyl-1,2,3,4-tetrahydro-9-thia-1,8-diazaanthracen-10-one 16g
Phosphorus oxychloride (3.1 g, 20 mmol) was added to chilled
1-benzyl-2-piperidone (1.9 g, 10 mmol) and the mixture was left at room
temperature overnight. The next day, 2-mercaptonicotinic acid (1.0 g,
6.7 mmol) was stirred into the mixture, and after 3 h the mixture was
added to ice (60 g) and ethyl acetate (40 mL). Sodium carbonate was
added in portions to pH 9, the organic phase separated, washed with
water (20 mL), and evaporated. The residue was chromatographed over
silica gel using dichloromethane and then dichloromethane contain-
ing 5, 10, and 15% ethyl acetate. The later fractions containing a spot
with pale blue fluorescence (silica TLC plates eluted with 10% ethyl
acetate/dichloromethane and visualized using 254 nm wavelength illu-
mination) were combined, the solvent was evaporated, and the residue
recrystallized from isopropyl alcohol to give the product 16g (0.58 g,
29%). A portion was recrystallized from isopropanol giving colour-
less needles, mp 152–154◦C. (Found: C 70.05, H 5.4, N 9.0, S 10.2.
C18H16N2O2S requires C 70.1, H 5.2, N 9.1, S 10.4%). δH 1.94–2.02
(2H, m, CH2CH2CH2), 2.82 (2H, t, J 6.2, NCH2CH2CH2), 3.41–3.47
(2H, m, NCH2), 4.75 (2H, s, ArCH2), 7.27–7.46 (6H, m, ArH and pyH),
8.56–8.61 (1H, m, pyH), 8.67–8.71 (1H, m, pyH). δC 20.6, 22.0, 50.6,
55.8, 108.0, 122.3, 126.5, 127.0, 128.0, 129.0, 135.3, 136.3, 150.9,
153.7, 155.5, 176.7. m/z (APCI) 309.0 [M + H]+.
A similar experiment using 1,4-dioxan as solvent afforded the same
compound in low yield (0.13 g, 4%).
Acknowledgments
Thanks to Mr Tony Wilson for technical assistance, to
Dr Gary Fallon for verification of the structure of 16h by
X-ray analysis, and to DuPont Agricultural Products (Stine–
Haskell, Delaware) for biological screening.
References
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[3] G. Eiden, H. Felbermeir, H. Buchborn, Arch. Pharm. (Weinheim)
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1-Benzyl-1,2,3,4-tetrahydro-9-thia-1,8-diazaanthracene-
10-thione 16h
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Phosphorus oxychloride (4.6 g, 30 mmol) was added to a mixture of
2-mercaptonicotinic acid (1.6 g, 10 mmol) and 2-benzyl piperidone
(1.9 g, 10 mmol) in sulfolane (10 mL), and stirred overnight. It was
then added to ice water (100 mL) and dichloromethane (50 mL), and
brought to pH 7 by portion-wise addition of solid sodium carbonate.
The organic phase was separated, washed with water (100 mL), then
allowed to partially evaporate (to ∼25 mL). The red crystals (0.17 g)
were filtered off and washed with benzene. A further quantity was
obtained by chromatography of the combined filtrate over silica gel with