Synthesis of benzisochalcogenol and -azole derivatives via ortho metalation of isophthalamides

Article abstract of DOI:10.1515/znb-1999-0812

The syntheses of benzofused isochalcogenazole derivatives via ortho-lithiation of isophthalamides is reported. N,N′-Dialkyl-isophthalamides, C₆H₄-1,3-(CONHR)₂, bearing R = iPr or tBu substituents are readily ortho metalate

Full text of DOI:10.1515/znb-1999-0812

Synthesis of Benzisochalcogenol and -azole Derivatives
via ortho Metalation of Isophthalamides
Berthold Kersting* and Michael DeLion
Institut für Anorganische und Analytische Chemie, Universität Freiburg,
Albertstraße 21, D-79104 Freiburg, Germany
* Reprint requests to Dr. B. Kersting. Fax: (+49) 761 203 6001.
E-mail: kerstber@sun2.ruf.uni-freiburg.de
Z. Naturforsch. 54 b, 1042-1047 (1999); received June 1, 1999
Isophthalamides, Metalation, Chalcogen, Insertion, Oxidation
The syntheses of benzofused isochalcogenazole derivatives via orf/?o-lithiation of isophtha-
lamides is reported. AUV'-Dialkyl-isophthalamides, C6H4-l,3-(CONHR)2, bearing R = /Pr or
fBu substituents are readily ortho metalated by using 3.3 equiv. of «-BuLi/TMEDA. The organo
lithium compounds react with S, Se, or Te to give 2-chalcogenol-isophthalamides, C6Hvl,3-
(CONHR)2-2-XH (X = S, Se, Te). Oxidation of the chalcogenols affords dichalcogenides under
acidic and benzisochalcogenazoles under basic conditions, respectively. The formation of the
five-membered heterocycles proceeds by disproportionation of the dichalcogenides. Oxidation
of the benzisothiazoles by hydrogen peroxide gives access to substituted sulfin- and sulfon-
amides.
Introduction
preparation and characterization of some oxidation
products of the initially obtained chalcogenol com-
pounds are also described.
Ortho-lithio benzamides (I) are useful reagents
in organic syntheses since they undergo reactions
with a variety of electrophiles [1]. They are also
valuable synthons for the preparation of sulfur het-
erocycles such as saccharine [2 - 4] and benzisoth-
iazole derivatives [5]. The ortho position in isoph-
thalamides, CöH4-1 ,3 -(CONHR)2 (II), is expected
to be even more activated towards C-H deprotona-
tion, however, only few studies on the preparation
and reactivity of o-lithio isophthalamides have ap-
peared in the literature [6 , 7]. This is true in partic-
ular for o-lithio isophthalamides of primary amines
and their reactions with elemental sulfur, selenium
[8 ], and tellurium [9].
Results and Discussion
Syntheses
o-Lithiation of the readily available N,N'-di-a\-
kylisophthalamides la,b (R = /Pr, fBu) proceeded in
good yields by using three equivalents of «-butylli-
thium/TMEDA (AWA^N'-tetramethyl-ethylenedi-
amine) as metalating agent (see Scheme 1). Depro-
tonation occurs initially at the relatively acidic pri-
mary amide protons, thereby consuming two equiv-
alents of the metalating agent, before C-H deproto-
nation takes place. The reaction is applicable, how-
ever, only for the /Pr and fBu derivatives. The lower
A^N'-di-alkylisophthalamides (R = Me, Et) could
not be metalated, presumably due to insufficient
solubility in tetrahydrofuran. This could easily be
monitored by the color changes that occurred during
the metalations. Addition of the metalating agent to
THF solutions of la,b produced brick-red solutions,
whereas no such effect was observed for the lower
isophthalamides. Since the resulting reaction mix-
tures are very air and moisture sensitive, they were
used directly in the next steps without isolation of
the trilithium salts, U 3 (la.b).
CONHR
II
Fig. 1. o-Lithio benzamides and o-lithio isophthalamides.
In the present study we describe i) the condi-
tions required for successful metalation of N,N'-di-
alkylisophthalamides, ii) the regioselectivity of the
metalations, and iii) reactions of sulfur, selenium,
and tellurium with the aryl lithium compounds. The
K
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B. Kersting and M. DeLion • Benzisochalcogenol and -azole Derivatives
1043
CONLiR
, Li
CONHR
CONHR
,X
CONLiR
Li3[1a,b]
CONHR
a: R = /'Pr
CONHR
1a,b
2a,b (X = D)
3a,b (X = SH)
4a (X =SeH)
5a (X = TeH)
b: R = ffiu
Scheme 1. Preparation of o-lithio isophthalamides and
2-chalcogenol-isophthalamides. i) 3.3 equiv. n-BuLi/
TMEDA, -70 °C -► +25 °C; ii) D.O, HCl; iii) S, Se,
or Te, HCl.
o-Lithiation in the present MN'-di-alkyliso-
phthalamides can in principle take place at the
arene carbon atoms C4 or C2. C-H deprotona-
tion at C2 should be preferred over deprotona-
tion at C4 since the former is activated by both
CONHR substituents. This was unambiguously
confirmed by a CH/CD exchange experiment. Thus,
treatment of the trilithium compounds with deu-
terium oxide gave exclusively 2-deuterio-AUV'-di-
alkyl-isophthalamides (2a,b), proving that C-H de-
protonation had occurred regioselectively at C2.
Contrary to our findings, metalation of N,N'-d\-n-
butylisophthalamide has been reported to occur at
the C4 position [6 , 7].
As expected for organo-lithium compounds,
trilithium salts L13 (la,b) readily reacted with ele-
mental sulfur, selenium, or tellurium to give the cor-
responding C2-X compounds (X = SH, SeH, TeH)
after hydrolysis. All chalcogenols were found to
be very air-sensitive. They were only isolated and
characterized in the case of X = SH (3a,b). The
corresponding selenol (4a) and tellurol compounds
(5a) were allowed to oxidize in the presence of air
(see below).
In accordance with the Cjy symmetric structures
of thiols 3a,b only four resonances for the six arene
carbon atoms are observed in the 13C NMR spec-
tra. Six signals were to be expected for the C4-SH
compounds. The SH proton in 3a,b appears as a
rather broad 1H NMR resonance at 6 k 5.7 to 5 .8 -
even in [Dlö-DMSO solution - presumably due to
intramolecular hydrogen bonding interactions with
the carbonyl groups. It is readily deprotonated and
the corresponding thiolate anion can be alkylated.
Treatment of 3b with allyl bromide in the pres-
Scheme 2. Preparation of disulfide 7 and benzisothiazoles
8a,b.
ence of K2CO3 , for example, gives the air-stable
thioether 6 .
Oxidation of chalcogenols
Compounds 3a,b are readily oxidized with a va-
riety of oxidants. The oxidation of 3a has been ex-
amined in more detail. Addition of FeI!1Cl3 -6 H2 0
(1 equiv.) in methanol produces the disulfide 7, but
only at pH values below 6 . In the presence of a
base the disulfide 7 readily disproportionates to give
equimolar quantities of the starting material 3a and
the benzisothiazole derivative 8a. Triethylamine as
a base is sufficient to bring about the disproportion-
ation and the whole process requires one equivalent.
Addition of further oxidant to the reaction mixture
results in complete formation of 8a. The dispro-
portionation of 7 may be explained by a mecha-
nism similar to one proposed by Reissert and Manns
[10, 11], and by McClelland [12]. Compounds 8a,b
could also be obtained by direct oxidation with io-
dine in the presence of NEt3 .
Similar to thiols 3a,b the compounds 4a and 5a
are oxidized in the presence of base to give the
benzisoselenazoles and -tellurazoles 9a and 10a, re-
spectively. It is assumed that these oxidations also
involve the formation of diselenide and ditelluride
intermediates, and that they disproportionate under
the basic reaction conditions.
CONHR
,SH
CONHR
8a,b (X = S)
9a (X = Se)
10a (X = Te)
( 1)
K2C 0 3
(X
CONHR
3b (R = ffiu)
CONHR
6(R = ffiu)
Fig. 2. Benzisochalgogenazoles 8a. b, 9a, and 10a.
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B. Kersting and M. DeLion • Benzisochalcogenol and -azole Derivatives
Experimental
1044
All manipulations with «-butyllithium were carried out
in an atmosphere of dry nitrogen by employing standard
Schlenk techniques. Starting chemicals were purchased
from Aldrich Chemicals and were used without further
purification. Solvents were dried using appropriate drying
agents and stored under nitrogen. Silica gel 60 (Merck,
230 - 400 mesh) was used for column chromatography.
The 1H and 13C NMR spectra were recorded on a Bruker
AC-200 instrument ('H: 200,13 MHz; l3C: 50,32 MHz).
CHN-Analyses: Perkin Elmer Elemental Analyzer 240.
IR: Bruker IFS25 spectrophotometer (KBr pellets).
A
Scheme 3. Preparation of sulfinamide 11a and sulfon-
amide 12a: i) H20 2/HAc, 25 °C; ii) H20 2/HAc, reflux,
60 min.
Compounds 8a,b and 9a are colorless air-stable
solids, the benzisotellurazole (10a) is pale-yellow.
Similar to other benzisothiazoles [13] compounds
8a,b exhibit two strong IR absorptions at« 1620 and
«1550 cm- 1 attributable to the carbonyl stretching
vibrations of the ring-CO (secondary amide, lac-
tame) and substituent-CO groups (primary amide).
In agreement with this assignment, the ring-CO ab-
sorption slightly shifts to lower frequencies with in-
creasing weight of the chalcogen atom, whereas the
other absorptions remain nearly unchanged (^(ring-
CO): 1619 (S), 1605 (Se), 1593 cm' 1 (Te); z>(sub-
stituent-CO): 1543 (S), 1546 (Se), 1554 (Te)).
N,N'-Di-isopropyl-isophthalamide (la)
A solution of isopropylamine (24.8 g, 0.42 mol) in
dichloromethane (50 ml) was slowly added to a solution
of isophthaloyl chloride (20.3 g, 0.10 mmol) in 200 ml
of dichloromethane at 0 °C and the resulting suspension
stirred for another 2 h. Water (200 ml) was then added
and the organic solvent removed under reduced pressure
resulting in the precipitation of the product as fine white
crystals. The crystalline mass was collected by filtration
and was washed several times with water. The pure prod-
uct was dried in an oven at 70 °C for 3 d. M.p. 182 -
184 °C. Yield 23.1 g (93%). IR (KBr, cm -'): v = 3251,
3075 i/(NH), 1628, 1562 u(CO). 'H NMR (DMSO-d6):
6 = 8.34 (d, V = 7.7 Hz, 2 H, NH), 8.26 (t, V = 2.0 Hz, 1
H, ArH), 7.94 (dd, 2J = 7.6 Hz, 4J = 2.0 Hz, 2 H, ArH),
7.50 (t, 2J = 7.6 Hz, 1 H, ArH), 4.09 (d spt, 2J = 1 Hz, 2
H, CH), 1.16 (d, V = 7 Hz, 12 H, C //3). 13C{'H} NMR
(DMSO-J6): <5= 165.1, 135.0, 129.5, 127.9, 126.3, 41.1,
22.2.
The oxidation of benzisothiazole 8a to cyclic
sulfin- and sulfonamides 11a and 12a, respectively,
has also been examined in this study. Both com-
pounds were obtained by oxidation of 8a with 30%
hydrogen peroxide in acetic acid. Compound 11a
formed at room temperature, compound 12a at el-
evated temperatures. The progress of the reaction
could easily be monitored by thin layer chromato-
graphy.
C 14H20N2O2 (248.33)
In contrast to 8a and 12a, the cyclic sulfinamide
11a contains an asymmetric sulfur atom. Therefore,
the methyl proton resonances of the prochiral iso-
propyl residues are expected to become inequivalent
and together with the methine protons should form
two A3 B3X systems. This is confirmed by 1H NMR
spectroscopy. The four inequivalent methyl groups
are also distinguished by four different l3C NMR
resonances in the 13C NMR spectrum of 11a.
Calcd C 67.72 H8.12 N 11.28%,
Found C 67.68 H8.10 N 11.16%.
N,N'-Di-tert-butyl-isophthalamide (lb)
This compound was prepared from rm-butylamine
(30.7 g, 420 mmol) and isophthaloyl chloride (20.3 g,
100 mmol) by the procedure detailed above for la. Trans-
parent needles. M. p. 208 - 210 °C. Yield: 26.5 g (96%). IR
(KBr, cm- 1): v = 3273, 3066 i/(NH), 1640, 1548 u(CO).
*H NMR (DMSO-d6): 6 = 8.11 (t, V = 2 Hz, 1 H, ArH),
7.85 (s, 2 H, NH), 7.86 (dd, 2J = 7.6 Hz, 4J = 2 Hz, 2
H, ArH), 7.45 (t, 2J = 7.6 Hz, 1 H, ArH), 1.37 (s, 18 H,
C //3). 13C{'H} NMR (CDCI3): 6 = 166.0, 135.9, 129.3,
128.6, 124.9,51.8,28.8.
In summary, the metalation of isophthalamides
by n-BuLi/TMEDA has been shown to proceed ex-
clusively at the C2 position. Subsequent reactions
with the elemental chalcogens followed by oxida-
tion results in the formation of the air-stable ben-
zisochalcogenols. This method thus provides a con-
venient alternative to the traditional synthesis of
such compounds.
C]6H24N20 2 (276.38)
Calcd C 69.53 H 8.75 N 10.14%,
Found C 69.45 H 8.62 N 9.86%.
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B. Kersting and M. DeLion • Benzisochalcogenol and -azole Derivatives
1045
2-Sulfanyl-N,N'-di-isopropyl-isophthalamide (3a)
H, NH), 7.96 (m, 2 H, Ar//), 7.54 (m, 1 H, Ar//), 4.09 (d
spt, V = 7 Hz, 2 H, CH), 1.16 (d, 37 = 7 Hz, 12 H, C //3).
A flask containing a mixture of la (4.97 g, 20.0 mmol),
TMEDA (7.67 g, 66.0 mmol), and 50 ml of THF was
placed in a dry-ice/2-propanol bath. To this suspension
was added via syringe /z-BuLi (26.4 ml of a 2.5 M solu-
tion in hexanes, 66.0 mmol) to give a bright-red solution.
The reaction mixture was allowed to warm to 25 °C at
which temperature it was stirred for a further 12 h. The
suspension was cooled to -60 °C and freshly sublimed
sulfur (641 mg, 20.0 mmol) was added in small portions.
The resulting suspension was stirred for lh at -60 °C and
then for 2 d at ambient temperature. The volatiles were
removed under reduced pressure and the resulting solid
hydrolyzed with 100 ml of water. After filtration, the pH of
the filtrate was adjusted to 1 by addition of 12 M HC1 and
the resulting brown solid isolated by filtration. The crude
product was redissolved in 1M NaOH, filtered, and the fil-
trate acidified to obtain 3a as an off-white solid. The solid
was collected by filtration, and dried over P4O 10. Yield:
4.48 g (80%). An analytical sample was obtained by col-
umn chromatography (Rf = 0.35, 10% MeOH/CHiCb).
IR (KBr, cm "1): v = 3274, 3061 i/(NH), 1630, 1538
HCO). 1H NMR (DMSO-^6): b = 8.39 (d, V = 7.7 Hz, 2
H, NH), 7.36 (m, 2 H, ArH), 7.18 (m, 1 H, ArH), 5.70 (s
br, 1 H, SH), 4.02 (dspt, 3J = 7.7 Hz, 2 H, CH), 1.13 (d,
V = 7.7 Hz, 12 H, CH},). 13C {!H} NMR (DMSO-d6) b =
167.3, 136.3, 130.5, 128.8, 124.2,41.1,22.2.
2-Deuterio-N',N'-di-tert-butyl-isophthalamide (2b)
This compound was prepared from lb (5.52 g,
20.0 mmol) by the procedure detailed above for 2a. 'H
NMR (DMSO-de): b = 7.92 (s, 2 H, NH), 7.87 (m, 2 H,
Ar//), 7.47 (m, 1 H, Ar//), 1.37 (s, 18 H, C //3).
Allyl-[2,6-di(N-tert-butyl-carbamoyl)phenyl] sulfide (6)
A suspension of 3b (308 mg, 1.00 mmol), allyl bromide
(133 mg, 1.10 mmol), and potassium carbonate (152 mg,
I.10 mmol) in acetone (10 ml) was stirred at r. t. for
12 h. To the solution was then added water to precipitate
crude 6. The solid was filtered, dried in air, and recrystal-
lized from ethyl acetate. Yield: 296 mg (85%). IR (KBr,
cm-1): v = 3299 i/(NH), 1646, 1528 v(CO). 'H NMR
(CDCI3): 6 = 7.47 (m, 2 H, Ar//), 7.30 (m, 1 H, Ar//),
6.10 (s br, 2 H, NH), 5.70 (m, 1 H, =CH), 4.86 (m, 2
H, =C //2), 3.42 (m, 2 H, SCH2), 1.41 (s, 18 H, C //3).
I3C {‘H} NMR (CDCI3): 6 = 167.4, 143.8, 133.2 (=CH),
129.2.128.8.126.5.118.0 (=CH2), 51.9,40.4 (CH2), 28.6.
C ,9H28N2 0 2S (348.50)
Calcd C 65.48 H8.10 N 8.04%,
Found C 65.32 H 8.02 N 7.76%.
C 14H20N2O2S (280.39)
Di(2,6-di(N-isopropyl-carbamoyl)phenyl)disulfide (1)
Calcd C 59.97 H7.19 N 9.99%,
Found C 59.83 H7.10 N 9.76%.
To a solution of 3a (280 mg, 1.00 mmol) in methanol
(10 ml) was added a solution of FeCl3-6H20 (270 mg,
1.00 mmol) in methanol (2 ml). After the reaction mix-
ture was stirred for 15 min, the solvent was removed
under reduced pressure. Water (25 ml) was added to
the residue, and the product extracted three times with
CH2CI2 (35 ml). The combined organic phases were dried
over M gS04, filtered, and evaporated to dryness. The pale
yellow solid was recrystallized from CH2Cl2/Et2 0 . Yield
0.26 g (93%). Rf = 0.37 (10% MeOH/CH2Cl2). IR (KBr,
cm-1): 3423, 3330, 3254 v(NH), 1647, 1533 z^(CO). 'H
NMR (CDCI3): b = 7.47 (m, 6H, Ar//), 6.58 (s br, 4H,
NH), 3.95 (m, 4H, CH), 1.12 (m, 24H. C //3). 13C{'H}
NMR(CDC13)<5= 167.2,143.3,130.3,129.6,129.4,42.1,
22.2.
2-Sulfanyl-N,N'-di-tert-butyl-isophthalamide (3b)
This compound was prepared from lb (5.52 g,
20.0 mmol) by the procedure detailed above for 3a. Yield:
5.05 g (82%). Rf = 0.35 (4% MeOH/CH2Cl2). IR (KBr,
cm-1): v = 3275, 3071 i/(NH), 1632, 1545 z/(CO). *H
NMR (DMSO-d6): b = 8.00 (s, 2 H, NH), 7.30 (m, 2 H,
Ar//), 7.14 (m, 1 H, Ar//), 5.80 (s br, 1 H, SH), 1.36 (s,
18 H, C //3). 13C{'H} NMR (CDCI3): 6 = 168.2, 137.1,
129.5, 128.5 (CH), 124.3 (CH), 52.0, 28.7.
C,6H24N20 2S (308.44)
Calcd C 62.31 H 7.84 N 9.08%,
Found C 62.13 H 7.70 N 8.76%.
C28H38N4O4S2 (558.75)
2-Deuterio-N,N'-di-isopropyl-isophthalamide (2a)
Calcd C 60.19 H 6.85 N 10.03%,
Compound la was metalated as described above. The
reaction mixture was hydrolyzed with D20 and then acid-
ified with 1 M HC1. The organic solvent was removed un-
der reduced pressure resulting in the precipitation of the
product as fine white crystals. The crystalline mass was
collected by filtration and was washed several times with
water. 'H NMR (DMSO-d6): b = 8.33 (d, V = 7.7 Hz, 2
Found C 60.14 H 6.70
N 9.86%.
Disproportionation o f 7
To a solution of 7 (0.28 g, 0.50 mmol) in methanol
(10 ml) was added a solution of NEt3 (50 mg, 0.50 mmol)
in methanol (1 ml). The resulting solution contained an
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1046
B. Kersting and M. DeLion • Benzisochalcogenol and -azole Derivatives
equimolar mixture of 3a and 8a (vide infra) as evidenced
placed in a dry-ice/2-propanol bath. To this suspension
was added via syringe n-BuLi (26.4 ml of a 2.5 M solution
in hexanes, 66.0 mmol) to obtain a bright-red solution.
The reaction mixture was allowed to warm to r. t., and the
resulting yellow suspension was stirred fur further 12 h.
Selenium (1.58 g, 20.0 mmol) was then added in small
portions at -76 °C. After being stirred for 2 further days
under N2, the flask was exposed to air for 5 d. The reaction
mixture was then acidified and the product extracted with
CH2C12. The organic phase was separated, dried with
M gS04, and the solvent removed in vacuum to give a
brown oil which was purified by column chromatography
(S i02, eluent 10%MeOH/CH2Cl2, Rf = 0.54). Yield: 3.0 g
(46%). IR (KBr, cm“ 1): 3264, 3076 i/(NH), 1607, 1547
u(CO). ' H N M R (CDCI3): 6 = 8.14 (d, 2J = 1.1 Hz, 1H,
Ar//), 7.98 (d, 2J = 7.7 Hz, 1H, Ar//), 7.46 (t, 2J = 7.7 Hz,
1H, Ar//), 7.11 (d, 2J = 7 Hz, 1H, N//CH), 4.78 (spt, V =
6.9 Hz, 1H, NCH), 4.34 (d spt, V = 7.0 Hz, 1H, NHC//),
1.41 (d, V = 7.0 Hz, 6H, C //3), 1.26 (d, 3J = 7.0 Hz, 6H,
C //3). 13C{'H} NMR (CDCI3): 6 = 165.7, 165.6, 141.1,
131.0, 130.6, 127.2, 126.1, 125.9, 46.1,42.8, 23.3,22.5.
by thin layer chromatography (3a: Rf = 0.35, 8a: Rf
0.54). Addition of iodine to the mixture resulted in com-
plete oxidation of 3a to give 8a as the sole product. The
product was precipitated by addition of H20 , filtered, and
dried in air. Yield: 251 mg (95%). The analytical data for
this material are identical to those of 8a (see below).
=
2-Isopropyl-7-(N-isopropyl-carbamoyl)benzisothiazole-
3-one (8a)
To a solution of 3a (280 mg, 1.00 mmol) in methanol
(10 ml) was added a solution of I2 (254 mg, 1.00 mmol) in
methanol (1 ml), followed by a solution of triethylamine
(202 mg, 2.00 mmol) in methanol (2 ml). The reaction
mixture was stirred for 30 min, water (10 ml) was added,
and the solution was acidified to pH = 1 by addition of
6M HC1. The resulting white precipitate was collected by
filtration. An analytical sample was obtained by column
chromatography (R, = 0.54, 10%MeOH/CH2Cl2). Yield:
0.26 g (93%). M. p. 198 - 200 °C. IR (KBr, cm ~1): 3276,
3079 i/(NH), 1619, 1547 v{CO). 'H NMR (CDCI3): 6 =
8.13 (d, 2J = 7.7 Hz, 1H, Ar//), 7.98 (d, 2J = 7.7 Hz, 1H,
Ar//), 7.40 (t, 2J = 7.7 Hz, 1H, Ar//), 7.02 (d, 2J = 1 Hz,
1H, NZ/CH), 4.91 (spt, V = 6.9 Hz, 1H, NC//), 4.35 (d
spt, V = 6.9 Hz, 1H, NHC//), 1.46 (d, 37 = 6.6 Hz, 6H,
C //3), 1.31 (d, V = 6.6 Hz, 6H, C //3). 13C{'H} NMR
(CDCI3): 6 = 164.9, 164.0, 141.8, 129.2, 127.7, 127.2,
125.0, 124.4, 45.8,42.5, 22.6, 22.2.
C |4H |8N20 2Se (325.27)
Calcd C 51.70 H 5.58 N8.61%,
Found C 51.48 H 5.32 N 8.43%.
2-Isopropyl- 7-(N-isopropyl-carbamoyl)benzisotellur-
azole-3-one (10a)
This compound was prepared as described above for 9a
from la and tellurium (2.00 g, 20.0 mmol). Yield: 1.96 g
(26%). IR (KBr, cm-1): 3236, 3064 i/(NH), 1595, 1554
//(CO). 'H NMR (CDCI3): 6 = 8.86 (d, 3J = 7.0 Hz, 1H,
NH), 8.50 (d, 2J = 7.7 Hz, 1H, Ar//), 8.14 (d, 2J = 7.7 Hz,
1H, Ar//), 7.39 (d, 2J = 1 Hz, 1H, NZ/CH), 4.44 (spt, V =
6.9 Hz, 1H, NC//), 4.38 (d spt, V = 7.0 Hz, 1H, NHC//),
1.31 (d, V = 7.0 Hz, 6H, C //3), 1.30 (d, 37 = 7.0 Hz, 6H,
C //3). ,3C{'H} NMR (CDCI3): 6 = 168.0, 166.9, 135.9,
132.8, 131.7 (CH), 129.0, 128.1 (CH), 127.4 (CH), 46.0,
43.3, 24.6, 22.5.
C,4Hi8N20 2S (278.37)
Calcd C 60.41 H 6.52 N 10.06%,
Found C 60.30 H6.31
N 9.83%.
2-tert-Butyl-7-(N-tert-butyl-carbamoyl)-benzisothiazole-
3-one (8b)
This compound was prepared from 3b (308 mg,
1.00 mmol) by the procedure detailed above for 8a. Yield:
278 mg (90%). IR (KBr, cm-1): 3275 i/(NH), 1622, 1542
v(CO). 1H NMR (CDCI3): 6 = 8.10 (d, 2J = 7.5 Hz, 1H,
Ar//), 7.69 (d, 2J = 7.5 Hz, 1H, Ar//), 7.42 (t, 2J = 7.5 Hz,
1H, Ar//), 6.30 (s, 1H, N//CO), 1.73 (s, 9H, C //3), 1.51
(s, 9H, C //3). 13C{’H} NMR (CDCI3): <5= 165.2, 164.7,
140.6,129.2,128.8 (CH), 127.2 (CH), 125.1 (CH), 124.8,
58.1,52.3, 28.9, 28.4.
Ci4H l8N20 2Te (373.91)
Calcd C 44.97 H 4.85 N 7.49%,
Found C 45.13 H 4.83 N7.31%.
2-isopropyl-7-(N-isopropyl-carbamoyl)benzisothi-
azole-1,3-dione (11a)
Ci6H22N20 2S (306.42)
Calcd C 62.72 H 7.24 N9.14%,
Found C 62.34 H7.31 N9.13%.
To a solution of 8a (278 mg, 1.00 mmol) in acetic
acid (3 ml) was added 30% aqueous hydrogen peroxide
(1 ml). After stirring for 12 h at r. t., water (25 ml) was
added, and the product extracted three times with CH2C12
(35 ml). The combined organic phases were washed with
1 M NaHC03, dried over M gS04, filtered and evapo-
rated to dryness. The pale yellow solid was recrystal-
2-Isopropyl-7-(N-isopropyl-carbcimoyl)benzisoselen-
azole-3-one (9a)
A flask containing a mixture of la (4.97 g, 20.0 mmol),
TMEDA (7.67 g. 66.0 mmol), and 50 ml of THF was
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B. Kersting and M. DeLion • Benzisochalcogenol and -azole Derivatives
1047
lized from CHCI3. Yield 261 mg (89%). Rf = 0.41 (4%
MeOH/CH2Cl2). IR (KBr, cm“ 1): 3332, 3077 i/(NH),
1701,1639,1550i/(CO), 1080*/(s0). 'H N M R (C D C 13):
6 = 8.03 (dd, 2J = 7.5 Hz, 4J = 2.7 Hz, 1H, Ar//), 7.92 (dd,
2J = 7.5 Hz, AJ = 2.7 Hz, 1H, Ar//), 7.72 (t, 2J = 7.5 Hz,
1 H, Ar//), 6.69 (d, 3/= 5.5 Hz, 1H, CON/f), 4.67 (spt, V =
6.9 Hz, 1H, CH), 4.33 (d spt, V = 7.5 Hz, 1H, CH), 1 .59
(d, V = 6.5 Hz, 3H, C //3), 1.57 (d, V = 6.5 Hz, 3H, C //3),
1.33 (d, V = 6.5 Hz, 3H, C //3), 1.29 (d, V = 6.5 Hz, 3H,
C //3). 13C{'H} NMR (CD3OD): <5= 165.9, 164.7, 146.1,
135.8, 134.8, 132.4, 131.4, 129.1, 48.2, 43.5, 22.6, 22.5,
22.4.21.8.
2-isopropyl-7-(N-isopropyl-carbamoyl)benzoisothi-
azole-1,1,3-trione (12a)
To a solution of 8a (278 mg, 1.00 mmol) in acetic
acid (3 ml) was added 30% aqueous hydrogen peroxide
(5 ml). After the reaction mixture was refluxed for 1 h,
water (25 ml) was added, and the product extracted three
times with CH2C12 (35 ml). The combined organic phases
were washed with 1 M NaHC0 3, dried over MgSO_t,
filtered, and evaporated to dryness. The pale yellow solid
was recrystallized from CHCI3. Yield: 284 mg (92%).
IR (KBr, cm-1): 3305, 3081 i/(NH), 1725, 1636, 1552
u(CO), 1346, 1182 i/(SO). 'H NMR (CDCI3): 6 = 8.13
(d, 2J = 7.5 Hz, 1H, Ar//), 8.01 (d, 2J = 7.5 Hz, 1H,
Ar//), 7.76 (t, 2J = 7.5 Hz, 1H, Ar//), 6.93 (s br, 1H,
CONH), 4.45 (spt, V = 6.8 Hz, 1H, CH), 4.21 (d spt, V =
6.7 Hz, 1H, CH), 1.54 (d, 3J = 6.8 Hz, 6H, C //3), 1.21
(d, V = 6.8 Hz, 6H, C //3). I3C{'H} NMR (CDC13): b =
161.6, 157.8, 134.7, 134.5, 134.1, 130.9, 127.7, 126.6,
47.2, 42.6, 22.0, 20.1.
Ci4H 18N2C>3S (294.37)
Calcd C 57.12 H6.16 N 9.52%,
Found C 57.03 H6.14 N 9.40%.
2-tert-Butyl-7-(N-tert-butyl-carbamoyl)benzisothi-
azole-l,3-dione (11b)
This compound was prepared from 8b (308 mg,
1.00 mmol) by the procedure detailed above for 8a. Yield:
245 mg (76%). 'H NMR (CDCI3): 6 = 7.99 (dd, 2J =
7.5 Hz, V = 2.7 Hz, 1 H, Ar//), 7.89 (dd, 2J = 7.5 Hz, V =
2.7 Hz, 1H, Ar//), 7.73 (t, 2J = 7.5 Hz, 1H, Ar//), 6.50
(br s, 1 H, CONH), 1.75 (s, 9H, C //3), 1.51 (s, 9H, C //3).
‘‘^C l'H } NM R(CD3OD): 6 = 168.0, 166.5, 145.9, 135.6,
134.5, 133.8, 132.9, 129.7, 60.5, 55.3, 30.2, 29.8.
C,4H,8N20 4S (310.37)
Calcd C 54.18 H 5.85 N 9.03%,
Found C 54.31 H 6.01 N 8.78%.
Acknowledgements
This work was supported by the Deutsche Forschungs-
gemeinschaft. Financial support from the Wissenschaft-
liche Gesellschaft, Freiburg, is also gratefully acknow-
ledged. M. D. thanks the Indiana-Purdue-Ohio State Pro-
gram for a fellowship.
Ci6H22N203S (322.42)
Calcd C 59.60 H 6.88 N 8.69%,
Found C 59.43 H 6.64 N 8.44%.
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