Phthalimidesulfenyl chloride 12: Generation and trapping of para- monothioquinones

Article abstract of DOI:10.1055/s-1999-3504

The reaction of phthalimidesulfenyl chloride 7 with o,o'-disubstituted phenols affords p-hydroxythiophthalimides which are the precursors of the corresponding p-thioquinones. The latter species are generated under mild conditions and efficiently trapped w

Full text of DOI:10.1055/s-1999-3504

1046
PAPER
Phthalimidesulfenyl Chloride 12:1 Generation and Trapping of
para-Monothioquinones
Beatrice Cantini, Giuseppe Capozzi,* Stefano Menichetti,* Cristina Nativi
Centro C. N. R. "Chimica dei Composti Eterociclici". Dipartimento di Chimica Organica, Universita’di Firenze, via G. Capponi 9, I-50121,
Firenze Italy
Fax +39(55)2476964; E-mail: capozzi@chimorg.unifi.it
Received 14 December 1998; 22 January 1999
which react as electron-poor dienophiles or heterodienes
Abstract: The reaction of phthalimidesulfenyl chloride 7 with o,o’-
in direct or inverse electron demand Diels–Alder reac-
tions.
disubstituted phenols affords p-hydroxythiophthalimides which are
the precursors of the corresponding p-thioquinones. The latter spe-
cies are generated under mild conditions and efficiently trapped
with 1,3-dienes.
O
O
O
Key words: phthalimidesulfenyl chloride, p-thioquinones, hetero
Diels–Alder reaction, spiro dihydrothiopyrans, desulfurization
Z
Z
N
S
S
S
Cl
O
Z = R, H
7
9
8
O
SO2R
O
In contrast to p-quinones the corresponding monothionat-
ed compounds, namely p-monothioquinones, are very
elusive species. In particular, as unique example, the par-
ent p-monothiobenzoquinone 1 has been pyrolytically ob-
tained and spectroscopically identified in argon matrix at
4oK.2 Other examples of such species available in the lit-
erature have been revealed to be misinterpreted.3 On the
other hand the crystalline stable p-thioanthraquinone (2)
has been prepared by heating 10-diazoanthrone (3) with
elemental sulfur in DMF,4,5 or reacting thiophthalimide
derivative 4 with tertiary bases.6 In both cases the dieno-
philic carbon–sulfur double bond of 2 was shown to
be able to react with electron-rich dienes, such as 2,3-
dimethylbuta-1,3-diene (5), to give spiro cycloadducts of
type 6.4–6
O
S
N
O
O
OR
Y
EDG
S
11
S
10
12
EDG = R, OR
Y = R, OR, SR
In particular o-thioquinones 12 are generated by reacting
o-hydroxythiophthalimides 13 in chloroform at 60 C
o
with tertiary bases, like pyridine, and are directly trapped
by electron-rich dienes or dienophiles (Scheme 1) to give
spiro dihydrothiopyrans or 1,4-benzoxathiins respective-
ly.1,11 The selective ortho-sulfenylation of phenols with 7
affords derivatives 13 in high yields (Scheme 1).1,12
S
S
N2
OH
O
S
OH
Py, CHCl3, 60 o
C
7
SNPhth
EDG
EDG
O
EDG
13
12
O
O
O
1
2
3
NPhth
S
EDG
EDG
S
S
O
5
O
S
X
S
EDG
O
12
O
X
4
6
X = OR, SR, NCOR, Ar
Scheme 1
In the last few years we have demonstrated the utility of
the phthalimidesulfenyl chloride (7) (PhthNSCl, Phth =
phthaloyl) for the generation of several a-functionalized
thiocarbonyl compounds such as a-oxothiones7 8,
a-sulfines8 9, a,a’-dioxothiones9 10, a-iminothiones10 11
and o-thioquinones1,11 12. These are useful intermediates
Thus the possibility to drive the substitution of the thio-
phthalimido moiety para to the hydroxy group could end
up with the formation of p-thioquinone derivatives.
Synthesis 1999, No. 6, 1046–1050 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Phthalimidesulfenyl Chloride 12: Generation and Trapping of para-Monothioquinones
1047
Table 1 Effect of Base and Temperature on the Synthesis of 15a.
In this paper we report our methodology for the prepara-
tion of valuable precursors of p-monothioquinones which
can be generated under mild conditions and trapped as
electron-poor dienophiles. The reaction of phthalimide-
sulfenyl chloride 7 with 2,6-dimethylphenol and 2,6-di-
tert-butylphenol occurs smoothly in chloroform at room
temperature to give the corresponding 4-hydroxy-3,5-di-
alkylthiophthalimides 14a,b in almost quantitative yields
(Scheme 2).
En- Base
Reaction Conditions
Yield
(%)a
try
(equiv)
Solvent
Temp
(oC)
Time
(h)
1
2
3
4
5
6
7
8
pyridine (1)
pyridine (2)
pyridine (1)
pyridine (1)
DBU (1)
Et3N (1)
Et3N (1)
Et3N (0.2)
CHCl3
CHCl3
benzene
tolnene
CHCl3
CHCl3
CHCl3
CHCl3
60
60
80
110
60
60
80
80
80
80
1
1
7.5
24
12
14
18
32
69
65
93
90
23
23
R
R
OH
R
OH
R
7, CHCl3, r.t.
a Isolated yield of 15a after column chromatography.
PhthNS
14a,b
14a: R = Me, 22h, 99%
14b: R = t-Bu, 26h, 98%
in very good yields even working at room temperature and
with catalytic amounts of base (Table 1).
Scheme 2
The generality of this approach for the generation of di-
enophilic p-thioquinones was simply demonstrated since,
in our optimized reaction conditions (Table 1, Entry 7), it
was possible to obtain from thiophthalimides 14b the cor-
responding thioquinone 16b which reacted with 5 to give
the cycloadduct 15b, isolated in 85% yield. Moreover
thione 16a reacted with cyclohexa-1,3-diene and 2-meth-
ylbuta-1,3-diene (isoprene) affording spiro derivatives 17
and 18 in 80% and 98% yields, respectively. Derivative
18 was obtained as a 7:1 mixture of regioisomers. The rel-
ative regiochemistry of compounds 18 was determined by
the analysis of their 1H NMR. spectra in comparison with
those of similar mixtures deriving from the reaction of
isoprene with different thiocarbonyl compounds13.
Compounds 14 are crystalline solids which can be puri-
fied by column chromatography and stored at room tem-
perature for several months without decomposition.
We decided to verify the possibility to use derivatives 14
to generate p-thioquinones using the same reaction
conditions which were effective for the formation of
o-thioquinones12 (see Scheme 1). Thus thiophthalimide
14a was heated at 60 oC in chloroform in the presence of
1 equivalent of pyridine and 2,3-dimethylbuta-1,3-diene
(5) as trapping reagent (Scheme 3).
O -
OH
Base
O
O
S
PhthNS
NPhth
14a
S
- PhthN -
O
S
15b
16b
O
O
O
O
5
S
S
7 : 1
16a
S
S
S
Scheme 3
17
18
In this case, however, even using an excess of pyridine,
high temperature and prolonged reaction time, we ob-
tained only poor yield of the spiro dihydrothiopyran 15a,
which is the result of the cycloaddition reaction of dieno-
philic p-thioquinone 16a with the diene 5, while large
amounts of unreacted thiophthalimide 14a were recov-
ered from the reaction mixtures (Scheme 3, Table 1).
Figure 3
A peculiar result arose when we tried to extend this meth-
odology to other aromatic systems. When sulfenyl chlo-
ride 7 was reacted with 2-methyl-1-naphthol (19) we
observed the formation of an equimolar mixture of the ex-
pected thiophthalimide 20 and a,b-unsaturated ketone 21.
The latter is clearly derived from the attack of 7 at the me-
thyl-substituted site of 19 with elimination of HCl.
Nevertheless using stronger tertiary bases like triethyl-
amine or DBU it was possible to isolate cycloadduct 15a
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1048
B. Cantini et al.
PAPER
Since N-thiophthalimide 20 was unstable on silica gel, its
ability to generate the corresponding p-thionaphthoquino-
ne 22 was verified by adding triethylamine and diene 5 to
the crude reaction mixture. Under these reaction condi-
tions a mixture of cycloadduct 23 (38%) and unaltered 21
(42%) was isolated (Scheme 4).
OH
O
Raney Ni, THF, r.t., 30 min.
48%
15a
H
25
OH
O
Raney Ni, THF, r.t., 30 min.
54%
23
H
26
Scheme 5
complex mixture of compounds. The presence, among the
other products, of the expected N-thiophthalimide 24 was
however confirmed since by adding Et3N and 5 to the re-
action mixture we isolated the cycloadduct 6,4,6 albeit in
very low yield (10%).
Scheme 4
As an application to this simple access to p-thioquinones
cycloadducts 15a and 23 were reacted with Raney Nickel
in THF at room temperature. As reported in Scheme 5 the
Another intriguing result was obtained when we tried to
apply this methodology to the preparation of monothioan-
thraquinone 2.4,6 The reaction of 7 with 9-anthrol gave a
Table 2 Spectroscopic Data of Spiro Cycloadduts 6, 15a, 15b, 17, 18, and 23.
Cycload-
duct
MS
m/z (%)]
1H NMR (CDCl3)
d, J (Hz)]
13C NMR (CDCl3)
d
6
306 (M+., 2),
224 (45),
84 (100)
1.67 (br s, 3H), 1.97 (br s, 3H), 2.80 (br s, 2H), 3.22
(br s, 2H), 7.41–7.64 (m, 4H), 7.83–7.88
(m, 2H), 8.28-8.34 (m, 2H)a
15a
15b
17
234 (M+., 9),
86 (100).
1.72 (br s, 3H), 1.83 (br s, 3H), 1.91 (br s, 6H), 2.32
(br s, 2H), 3.25 (br s, 2H), 6.70 (br s, 2H)
16.1, 19.3 (q), 20.4 (q), 30.3 (t), 41.2 (t), 42.4
(s), 122,7 (s), 124,9 (d), 134.3 (s), 145.3 (s),
186.2 (s)
318 (M+., 13),
303 (6), 236 (8),
84 (100).
1.22 (s, 18H), 1.72 (br s, 3H), 1.84 (br s, 3H), 2.30
(br s, 2H), 3.23 (br s, 2H), 6.60 (s, 2H)
19.3, 20.4 (q), 29.3 (q), 30.6 (t), 34.7 (s),
42.1(t), 42.6 (s), 123.8 (s), 125.3 (d), 141.5 (s),
146.1 (s), 185.5 (s)
232 (M+., 4),
152 (13),
79 (100).
1.28–1.47 (m, 1H), 1.65–1.79 (m, 1H), 1.82 (d, 3H,
J = 1.6), 1.91 (d, 3H, J = 1.6), 2.10–2.27 (m, 2H),
2.66–2.71 (m, 1H), 3.58–3.66 (m, 1H), 6.36–6.44
(m, 1H), 6.52–6.58 (m, 1H), 6.61–6.69 (m, 1H),
7.10–7.14 (m, 1H)
15.9, 16.8 (q), 20.0, 28.4 (t), 35.3 (d), 39.6 (d),
53.0 (s), 131.6 (s), 133.2, 134.1, 134.3 (d),
145.9, 148.2 (s), 186.1 (s)
18
23
Major: 220
(M+., 56),
205 (7),
146 (11),
84 (100).
Major: 1.85 (s, 3H), 1.91 (s, 6H), 2.36–2.41 (m, 2H),
3.24 (s, 2H), 5.55–5.60 (m, 1H), 6.72 (s, 2H).
Minor: 1.75 (s, 3H), 1.91 (s, 6H), 2.26 (s, 2H), 3.35–
3.38 (m, 2H), 5.70–5.78 (m, 1H), 6.72 (s, 2H)
Major: 16.1 (q), 24.1 (q), 28.7 (t), 35.2 (t), 40.6
(s), 119.5 (d), 129.9 (s), 134.6, 134.7 (d), 144.9
(s), 186.1 (s)
270 (M+., 51),
188 (100)
1.74 (br s, 3H), 1.89 (br s, 3H), 2.03 (d, 3H, J = 1.4),
2.12–2.27 (m, 1H), 2.97–3.20 (m, 2H), 3.54–3.64
(m, 1H), 6.95–7.01 (m, 1H), 7.39–7.47 (m, 1H),
7.55–7.63 (m, 1H), 7.71–7.76 (m, 1H), 8.21 (dd, 1H,
J = 1.6, 8.8)
16.3, 19.3 (q), 20.5 (q), 31.8 (t), 42.0 (t), 44.0
(s), 122,5, 126.1, 131.2 (s), 127.0, 127.5,
127.8, 132.5 (d), 131.8 (s), 144.5 (d), 145.4 (s),
184.5 (s).
a Lit.4 1H NMR (60 MHz, CDCl3/TMS): d = 1.69 (s, 6H), 2.75 (s, 2H), 3.21 (s, 2H).
Synthesis 1999, No. 6, 1046–1050 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Phthalimidesulfenyl Chloride 12: Generation and Trapping of para-Monothioquinones
1049
Thiophthalimide 21
Pale yellow solid; mp 149–151°C.
NPhth
S
IR (KBr pellet): n = 2923 (CH), 1784, 1740 (amide C=O), 1714
(C=O), 1667 cm–1 (C=C).
1H NMR: d = 1.72 (s, 3 H), 6.09 (d, 1 H, AB system, J = 9.6 Hz),
6.75 (d, 1 H, AB system, J = 9.6 Hz), 7.10–7.15 (m, 1 H), 7.40–7.56
(m, 2 H), 7.73–7.78 (m, 2 H, Phth), 7.84–7.89 (m, 2 H, Phth), 8.02–
8.15 (m, 1 H).
OH
24
Figure 4
13C NMR: d = 20.2 (q), 59.6 (s), 124.0 (d), 127.5, 128.3, 129.2,
129.3, 130.8, 134.1 (d), 129.6 (s), 131.6 (d), 134.6 (d), 136.1 (s),
167.6 (s), 194.1 (s). MS: mz (%) = 335 (M+., 5), 188 (23), 157 (100),
147 (27).
expected desulfurization, which occurred without affect-
ing the exocyclic carbon–carbon double bond, was fol-
lowed by a spontaneous aromatization allowing the
isolation of the allyl substituted phenols 25 and 2614
(Scheme 5).
Anal. C19H13NO3S: Calcd. C, 68.04; H, 3.91; N, 4.18. Found C,
68.33; H, 3.78; N, 4.02.
Spiro Cycloadducts 6, 15a, 15b, 17, 18 and 23: General Proce-
dure
In conclusion we have shown that phthalimidesulfenyl
chloride 7 and o,o’-disubstituted phenols can be used as
key reagents for the preparation of p-thioquinones. In sev-
eral cases these species are generated and trapped in al-
most quantitative yields and under mild reaction
conditions.
To a solution of N-thiophthalimide in anhyd CHCl3 were added suc-
cesively the appropriate diene (2 equiv) and Et3N (1 equiv). The
mixture was kept at r.t. until the complete disappearance of the
1
thiophthalimide, monitored by TLC and/or H NMR spectroscopy.
Evaporation of the solvent and flash chromatography allowed the
isolation of cycloadducts 6,4 15a, 15b, 17, 18 and 23. Spectroscopic
data are reported in Table 2. Derivatives 15a, 15b, 17, 18 and 23
gave satisfactory microanalyses (± 0.4%) (Table 2).
Further applications of the chemistry of 7 to the synthesis
of functionalised thiocarbonyl compounds are under in-
vestigation in this laboratory.
Desulfurization of Cycloadducts 15a and 23: General Proce-
dure
To a solution of the spirocycloadduct 15a or 23 (0.1 mmol) in anhyd
THF (1 mL) was added activated Raney Nickel15 (0.3 mL) and the
mixture stirred at r.t. for 30 min. The crude mixture was diluted with
CH2Cl2 (20 mL) filtered through Celite and evaporated to dryness.
Purification of the phenols 25 and 26 was achieved by flash chro-
matography.
1H and 13C spectra were recorded in CDCl3 at 200 MHz using the
residual CHCl3 at d = 7.26 as reference. Melting points are uncor-
rected. CHCl3, CH2Cl2, THF, pyridine and triethylamine were dried
following standard procedures, all commercial reagents were used
without further purification as obtained from freshly opened con-
tainers. Petroleum ether used had bp 40–70 °C. Phthalimidesulfenyl
chloride 7 was prepared as reported elsewhere.1
4-(2,3-Dimethylbut-2-enyl)-2,6-dimethylphenol (25)
Petroleum ether/EtOAc (5:1); yield: 48%; orange oil.
1H NMR: d = 1.58 (br s, 3 H), 1.72 (br s, 3 H), 1.79 (br s, 3 H), 2.22
Compounds 14a, 14b, 20, 21 and 24
The reaction of 7 with the required phenol was performed as previ-
ously reported.1 In the case of 14a, 14b and 21 isolation was
achieved by flash chromatography (CH2Cl2). Thiophthalimides 20
and 24 were not isolated due to their instability on silica gel and the
crude mixtures were directly treated with Et3N to generate the cor-
responding p-thioquinones. Data of compounds 14a, 14b and 21 are
as follows:
(s, 6 H), 3.26 (s, 2 H), 4.50 (br s, 1 H, OH), 6.75 (s, 2 H).
13C NMR: d = 18.2 (q), 20.6 (q, 3 CH3), 39.1 (t), 109.0 (s), 122.7 (s),
125.2 (s), 128.5 (d), 132.5 (s), 150.2 (s).
MS: m/z (%) = 204 (M+., 28), 122 (22), 84 (100). Anal. C14H20O:
Calcd. C, 82.30; H, 9.87. Found C, 82.47; H, 9.69.
4-(2,3-Dimethylbut-2-enyl)-2-methylnaphthol (26)
N-(3,5-Dimethyl-4-hydroxyphenylthio)phthalimide (14a)
Petroleum ether/EtOAc 10:1 (53%); red glassy solid.
White solid; mp 173–175 °C.
1H NMR: d = 2.20 (s, 6 H), 4.97 (s, 1 H, OH), 7.47 (s, 2 H), 7.67–
7.76 (m, 2 H, Phth), 7.85–7.92 (m, 2 H Phth).
1H NMR: d = 1.60 (br s, 6 H), 1.80 (br s, 3 H), 2.38 (s, 3 H), 3.73
(br s, 2 H), 4.95 (s, 1 H, OH), 6.95 (s, 1 H), 7.43–7.51 (m, 2 H),
7.91–7.97 (m, 1 H), 8.16–8.19 (m, 1 H).
13C NMR: d = 15.7 (q), 123.8 (d), 124.0 (d), 124.4 (s), 132.0 (s),
MS: m/z (%) = 240 (M+., 12), 225 (7), 158 (32), 41 (100).
134.4 (d), 135.3 (s), 154.5 (s), 168.0 (s).
Anal. C17H20O: Calcd. C, 84.96; H, 8.39. Found C, 85.11; H, 8.22.
MS: m/z (%) = 299 (M+., 5), 147 (39), 76 (100). Anal. C16H13NO3S:
Calcd. C, 64.20; H, 4.38; N, 4.68. Found C, 64.00; H, 4.60; N, 4.20.
Acknowledgement
N-(3,5-Di-tert-butyl-4-hydroxyphenylthio)phthalimide (14b)
Pale yellow solid; mp 215–217 °C.
1H NMR: d = 1.41 (s, 18 H), 5.50 (s, 1 H, OH), 7.67–7.82 (m, 4 H),
7.84–7.96 (m, 2 H).
13C NMR: d = 30.0 (q), 34.3 (s), 123.8 (d), 124.2 (s), 132.2 (s), 132.8
(d), 134.3 (d), 136.8 (s), 156.3 (s), 168.0 (s).
Work carried out in the framework of the National Project: "Stereo-
selezione in Sintesi Organica. Metodologie ed Applicazioni" sup-
ported by the Ministero dell'Università e della Ricerca Scientifica e
Tecnologica, Rome, and by the University of Florence.
MS: m/z (%) = 383 (M+., 16), 236 (16), 147 (100). Anal.
C22H25NO3S: Calcd. C, 68.90; H, 6.57; N, 3.65. Found C, 68.73; H,
6.80; N, 3.28.
Synthesis 1999, No. 6, 1046–1050 ISSN 0039-7881 © Thieme Stuttgart · New York

1050
B. Cantini et al.
PAPER
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(12) Capozzi, G.; Falciani, C.; Menichetti, S.; Nativi, C., Gazz.
Chim. It. 1996, 126, 227.
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literature procedure:
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Birmingham, AL, 1962, p 870.
Article Identifier:
1437-210X,E;1999,0,06,1046,1050,ftx,en;P06998SS.pdf
Synthesis 1999, No. 6, 1046–1050 ISSN 0039-7881 © Thieme Stuttgart · New York