Derivatives from isoselenocyanates: Synthesis of 2-phenyl-6H-[5,1,3] benzoselenadiazocine

Article abstract of DOI:10.1002/hlca.200490132

The reaction of N-phenylbenzimidoyl isoselenocyanates 8 with primary and secondary amines in acetone at room temperature, followed by treatment with a base, led to 6H-[5,1,3]benzoselenadiazocine derivatives of type 10 (Scheme 3). An analogous cyclization was observed when 8a and 8b were reacted with the Na salt of diethyl malonate in EtOH at room temperature, which yielded the eight-membered selenaheterocycles 11 (Scheme 5). The molecular structures of some of the products, as well as that of a sulfur analogue, have been established by X-ray crystallography (Figs. 1-4). The isoselenocyanates 8 have been prepared from N-(2-methylphenyl)benzamides 5 in a three-step procedure via the corresponding imidoyl chlorides 6, side-chain chlorination to give 7, and treatment with KSeCN (Scheme 2).

Full text of DOI:10.1002/hlca.200490132

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452
Helvetica Chimica Acta ± Vol. 87 (2004)
Derivatives from Isoselenocyanates: Synthesis of 2-Phenyl-6H-
[
5,1,3]benzoselenadiazocine
1
by Plamen K. Atanassov ), Anthony Linden, and Heinz Heimgartner*
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
The reaction of N-phenylbenzimidoyl isoselenocyanates 8 with primary and secondary amines in acetone at
room temperature, followed by treatment with a base, led to 6H-[5,1,3]benzoselenadiazocine derivatives of type
0 (Scheme 3). An analogous cyclization was observed when 8a and 8b were reacted with the Na salt of diethyl
1
malonate in EtOH at room temperature, which yielded the eight-membered selenaheterocycles 11 (Scheme 5).
The molecular structures of some of the products, as well as that of a sulfur analogue, have been established by
X-ray crystallography (Figs. 1 ± 4). The isoselenocyanates 8 have been prepared from N-(2-methylphenyl)benz-
amides 5 in a three-step procedure via the corresponding imidoyl chlorides 6, side-chain chlorination to give 7,
and treatment with KSeCN (Scheme 2).
1
. Introduction. ± The current interest in selenaheterocycles is mainly due to their
chemical properties [1 ± 3] and biological functions [4 ± 8] (see also references cited in
9 ± 14]). The main drawbacks of some syntheses are the toxicity of many commonly
[
used Se reagents and the instability of some intermediates. With the aim of developing
syntheses of new selenaheterocycles with less-toxic, conveniently accessible, and safely
usable Se reagents, we have investigated reactions with various isoselenocyanates. For
example, the reaction of aroyl isoselenocyanates with diazoacetate led to 1,2,3-
selenadiazoles [9], N-arylimidoyl isoselenocyanates were transformed into 2-amino-
1,3-selenazoles [10], and N-(4-nitrobenzyl)benzimidoyl isoselenocyanates, on treat-
ment with Et N, gave bis(2,4-diarylimidazoles-5-yl) diselenides [11]. Recently, we have
3
shown that aryl isoselenocyanates 1 are convenient, cheap, and safe Se reagents for the
preparation of selenazolo[5,4-b]pyridines 2 [12], 1H-[1,3,6]triazaaceanthrylene deriv-
atives 3 [13], and selenet-2(2H)-imines 4 [14] (Scheme 1).
In this paper, we report the results of the reaction of N-phenylbenzimidoyl
isoselenocyanates of type 8 with primary and secondary amines, and with the Na salt of
diethyl malonate, which leads to eight-membered selenaheterocycles (see [15]). An
analogous reaction has been recently used by Stankovsky and Spirkova to prepare
benzothiadiazocines [16].
2
. Results andDiscussion. ± According to a known procedure [17], N-[(2-
chloromethyl)phenyl]benzimidoyl chloride (7a) was prepared from N-(2-methylphen-
yl)benzamide (5a) by consecutive treatment in refluxing SOCl and with SO Cl in
2
2
2
boiling benzene in the presence of azobis[isobutyronitrile] (AIBN). To a stirred
solution of the crude 7a in dry acetone, a freshly prepared solution of 1.1 equiv. of
1)
Part of the Ph.D. thesis of P. K. A., Universit‰t Z¸rich, 2004.

Helvetica Chimica Acta ± Vol. 87 (2004)
1453
Scheme 1
KSeCN in dry actone was added at À 58 to 08, and the mixture was stirred at 08 for 1 h.
Then, the solvent was evaporated, the residue was dissolved in CHCl , the solid KCl
3
removed by filtration, and the solvent was evaporated in vacuo. The isoselenocyanate
8a obtained was used for the following reactions without further purification
(
Scheme 2).
Scheme 2

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Helvetica Chimica Acta ± Vol. 87 (2004)
Because of the relatively low yields of the products of the subsequent reactions and
the presence of some overchlorinated products (see later), we investigated the
formation of 6a and 7a in detail. We assumed that the treatment of 5a with SOCl led to
2
partial chlorination of the benzene ring to give a mixture of 6a and 6b. Therefore, the
product was hydrolyzed and analyzed. According to the elemental analysis, chlorina-
tion of the benzene ring occurred under the optimized reaction conditions (3 h) to an
extent of 1.5%.
The crude imidoyl chloride 6a (containing small amounts of 6b) was dissolved in
dry benzene and mixed with 3 equiv. of SO Cl and catalytic amounts of AIBN. The
2
2
mixture was refluxed for 4 h, the solvent and excess SO Cl were removed under
2
2
reduced pressure, the remaining oily product was distilled in vacuo (150 ± 1708), and the
1
fractions were analyzed by H-NMR. This step has been performed under different
conditions, varying the equiv. of SO Cl and the reaction time. Under the optimal
2
2
conditions (3 equiv. of SO Cl , 4 h), the mixture consisted of ca. 13.5% of 6a/6b, ca.
2
2
7
2% of 7a/7b, and ca. 13.5% of products with a Cl CH group. When the reaction was
2
carried out with 6b, the optimal conditions were 1.5 equiv. of SO Cl and 4-h reflux,
2
2
leading to a mixture of ca. 13.5% of the ClCH derivative.
2
The crude isoselenocyanate 8a was dissolved in acetone, and 0.9 equiv. of
morpholine, pyrrolidine, PhCH NH , and cyclohexylamine, respectively, were added
2
2
while stirring the mixture at room temperature. After 15 min, the precipitate was
removed by filtration, and the filtrate was allowed to stand for 24 h. Pale yellow
hydrochlorides 9 precipitated (Scheme 3). The free bases were obtained after
treatment of the hydrochlorides 9 with 1.5 ± 2 equiv. of (diisopropylamino)meth-
ylÀpolystyrene in CHCl at ambient temperature. The remaining oil was triturated
3
with MeOH, and pale yellow crystals of 10 were obtained (Table 1). It is important to
mention that the reaction failed when excess amine was added at once, or when Et N
3
was added before the addition of the primary or secondary amine. In other words, the
formation of eight-membered benzoselenadiazocines as HCl salts of type 9 seems to be
crucial.
Scheme 3

Helvetica Chimica Acta ± Vol. 87 (2004)
Table 1. Yields of Benzoselenadiazocines 10
1455
Compound
R1
R2
R3
Yield [%]a)
10a
10b
10c
10d
10e
H
H
H
H
Cl
À(CH
À(CH
2
2
)
)
2
O(CH
À
2
)
2
À
14.4
7.5
24.1
14.0
7.8
4
H
H
PhCH
Cyclohexyl
2
À(CH
2
)
4
À
a) With respect to crude 7a.
The structures of the products were established on the basis of their spectroscopic
data and elemental analyses, and, in the cases of 10a, 10c, and 10d, X-ray crystal-
structure determinations were carried out, confirming the proposed structures.
The crystal structure of 10a (Fig. 1) established the eight-membered 6H-
[
5,1,3]benzoselenadiazocine ring and, therefore, the ring closure between the Se-atom
and the CH Cl group. The crystal actually proved to be a co-crystal of composition
2
0
.94(C H N OSe) ¥ 0.06(C H ClN OSe) ¥ MeOH. This conclusion was based on the
19 19 3 19 18 3
observation that, although the initially developed structural model corresponded with
À3
the expected compound 10a, one peak of residual electron density of 1.9 e A
remained ca. 1.6 ä from C(9) of the phenyl ring. Given the chemical evidence, which
indicates that the crystals contain a small amount of a corresponding compound that is
Cl-substituted at C(9), the peak was assigned as a partial-occupancy Cl-atom. The site-
occupation factor of this Cl-atom was refined to a value of 0.060(2). Therefore, the
crystal appears to be a mixture of two compounds: ca. 94% is the expected compound
10a, while ca. 6% is the corresponding compound, which is Cl-substituted at C(9). The
asymmetric unit in the structure also contains one molecule of MeOH. The OH group
of the MeOH molecule forms an intermolecular H-bond with N(5) of the eight-
membered ring of the Se compound. This interaction links pairs of 10a and MeOH
together and has a graph set motif [19] of D.
The crystal structures of compounds 10c and 10d, obtained from the reaction of 8a
with PhCH NH and cyclohexylamine, respectively, revealed molecules that are very
2
2
similar to that of 10a (Fig. 2). There was no evidence for the presence of any C(9)-Cl-
substituted derivative in either of these structures. In the case of 10c, there was one
significant peak of residual electron density in the region of atoms C(8), C(9), and
C(10), but the position of this peak could not be correlated with any chemically sensible
atom, so the effect was ignored (see Exper. Part). In both structures, the NH group at
C(2) forms an intermolecular H-bond with the N(5)-atom of the eight-membered ring
of an adjacent molecule. These interactions link the molecules into extended chains,
which run parallel to the x-axis and z-axis, respectively, and have a graph set motif of
C(6).
Analogously to the synthesis of 10b, the Cl derivative 10e was prepared from 7b.
Treatment with KSeCN gave crude 8b (Scheme 2), which was reacted with pyrrolidine.
The hydrochloride 9e was deprotonated by treatment with polymeric base, and 10e was
obtained in low yield (7.8% with respect to crude 7b; Scheme 3).
For comparison, the analogous reaction was carried out with the benzimidoyl
isothiocyanate 11, which has been described previously [16]. The addition of 0.9 equiv.

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Helvetica Chimica Acta ± Vol. 87 (2004)
Fig. 1. ORTEP Plots [18] of the molecular structure of a) 10a and b) the chlorinated minor product (50%
probability ellipsoids; arbitrary numbering of atoms; the MeOH molecule is not shown)

Helvetica Chimica Acta ± Vol. 87 (2004)
1457
Fig. 2. ORTEP Plots [18] of the molecular structure of a) 10c and b) 10d (50% probability ellipsoids; arbitrary
numbering of atoms)
of morpholine to a solution of 11 in acetone at room temperature led to the formation
of a hydrochloride, which was transformed to the free base 12 (24.6%) by treatment
with polymeric base (Scheme 4). The structure of 12 was elucidated on the basis of the
spectroscopic data and was established by X-ray crystallography (Fig. 3). Again, the
crystal appeared to be a mixture of two compounds: ca. 96% is the expected 12, while

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458
Helvetica Chimica Acta ± Vol. 87 (2004)
Scheme 4
ca. 4% is the corresponding compound, which is Cl-substituted at C(9) of the phenyl
ring.
When 5 equiv. of morpholine were added at once to the solution of 11 in acetone at
room temperature, small amounts (10.6%) of the thiourea derivative 13 were isolated
2
as the only product (Scheme 4) ). For the formation of this product, two molecules of
morpholine have reacted with 11, i.e., one molecule underwent an addition to the NCS
group and the second one a replacement of the Cl-atom of the CH Cl group.
2
In addition to the reactions of 8 with amines as N-nucleophiles, we investigated the
corresponding reaction with C-nucleophiles, e.g., the Na salt of diethyl malonate. To a
solution of NaOEt in EtOH, diethyl malonate was added at room temperature,
followed by 8. After stirring for 24 h, the solvent was removed, and the residue was
dissolved in CHCl . Filtration and evaporation of the solvent gave an oil, which
3
solidified to give yellow crystals of the eight-membered product 14 (Scheme 5). This
reaction is analogous to the formation of 5,1,3-benzothiadiazocines from 11 and diethyl
malonate [16].
The elemental analyses and CI-MS were in accordance with the expected structure
1
4' (analogous to the proposed structure of the S analogue [16]). The IR spectrum
À1
À1
showed an intense absorption for CˆO at 1711 cm , but also a band at 3287 cm ,
which could be assigned to an NH group. This assumption was supported by an NH
1
13
absorption at 9.61 ppm in the H-NMR spectrum. In the C-NMR spectrum, the ester
CO groups absorb at 156.9 ppm, which indicates extensive conjugation. On the other
hand, a signal for a CH group, as in 14', was missing. Finally, the structure of 14a was
established by X-ray crystallography (Fig. 4).
As with the crystal structure of 10a, the structure of 14a revealed the presence of a
co-crystal comprising two compounds: ca. 96% is 14a, while ca. 4% is the correspond-
ing compound, which is Cl-substituted at C(9) of the phenyl ring. The NH group of the
molecule forms an intermolecular H-bond with the CˆO O-atom of one of the ester
2)
In the case of the Se analogue 8, no analogous product could be observed when excess morpholine was
used, and only extensive decomposition occurred.

Helvetica Chimica Acta ± Vol. 87 (2004)
1459
Fig. 3. ORTEP Plots [18] of the molecular structure of a) 12 and b) the chlorinated minor product (50%
probability ellipsoids; arbitrary numbering of atoms)
groups of a neighboring molecule. These interactions link the molecules into extended
chains, which run parallel to the z-axis and have a graph set motif of C(8).
In conclusion, we have shown that N-phenylbenzimidoyl isoselenocyanates react
with amines and C-nucleophiles to give 6H-[5,1,3]benzoselenadiazocines via a

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Helvetica Chimica Acta ± Vol. 87 (2004)
Scheme 5
nucleophilic addition to the heterocumulene moiety followed by cyclization. The yields
of the eight-membered products are only modest, mainly because of the difficulty of
preparing the starting N-[2-(chloromethyl)phenyl]benzimidoyl chloride selectively.
We thank the analytical sections of our institute for spectra and analyses and Miss Jovita Cavegn for her
assistance with the determination of the crystal structures. Financial support of the Swiss National Science
Foundation and F. Hoffmann-La Roche AG, Basel, is gratefully acknowledged.
Experimental Part
. General. See [9]. IR Spectra in KBr; H- and 13C-NMR spectra in CDCl
1
unless otherwise stated.
1
3
2
. Preparation of N-Phenylbenzamides. General Procedure. To a cooled soln. of o-toluidine (0.075 mol) in
pyridine (60 ml, ice bath), PhCOCl (10.96 g, 0.078mol) was added slowly under stirring. After 10 min, the ice-
bath was removed, and the mixture was stirred for 3 h at r.t. Then, cold H O (200 ml) was added, and the mixture
2
2
was stirred at 08 for 10 min. The solid material was filtered and washed several times with cold H O. The crude
product was recrystallized from EtOH.
N-(2-Methylphenyl)benzamide (5a). From 8.00 g (75 mmol) of o-toluidine and 10.96 g (78mmol) PhCOCl:
1
1
2.3 g (78%). White crystals. M.p. 144.0 ± 145.08 (EtOH). H-NMR: 8.00 ± 7.70, 7.60 ± 7.40, 7.30 ± 7.00
(
3m, 9 arom. H, NH); 2.28( s, Me).
N-(4-Chloro-2-methylphenyl)benzamide (5b). From 10.62 g (75 mmol) of 4-chloro-2-methylaniline and
1
1
0.96 g (78mmol) PhCOCl: 15.54 g ( 84 .4%). White crystals. M.p. 173.0 ± 173.9 8 (EtOH). H-NMR: 8.00 ± 7.70,
7.60 ± 7.40, 7.20 ± 7.00 (3m, 8arom. H); 7.61 ( s, NH); 2.21 (s, Me).

Helvetica Chimica Acta ± Vol. 87 (2004)
1461
Fig. 4. ORTEP Plots [18] of the molecular structure of a) 14a and b) the chlorinated minor product (50%
probability ellipsoids; arbitrary numbering of atoms)

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Helvetica Chimica Acta ± Vol. 87 (2004)
3. Preparation of N-[2-(Chloromethyl)phenyl]benzimidoyl Chlorides. A mixture of 5 and 2 ± 3 equiv. of
SOCl
2
was heated to reflux until the evolution of SO
2
ceased (3 h). The excess SOCl
2
was removed i.v. The
and a cat. amount of
Cl were
crude, oily imidoyl chloride 6 was dissolved in dry benzene, mixed with 3 equiv. of SO
azobis[isobutyronitrile] (AIBN), and the mixture was refluxed for 4 h. The solvent and excess SO
2
Cl
2
2
2
removed under reduced pressure, the remaining oily product was purified by distillation i.v. (b.p. 150 ± 1708/
1
0
.041 Torr), and the fractions were analyzed by H-NMR spectroscopy. Chlorination at C(4) of the benzene ring
connected to the N-atom was observed. According to the elemental analysis of the hydrolyzed product of 6a, ca.
.5% of the chlorinated product was present.
N-[2-(Chloromethyl)phenyl]benzimidoyl Chloride (7a): H-NMR: 8.20 ± 7.00 (m, 9 arom. H); 4.53
1
1
1
3
(
s, CH
2 2
Cl of 7a); 4.46 (s, CH Cl of 7b); 2.25 (s, Me of 6b); 2.15 (s, Me of 6a). C-NMR: 146.3 ± 120.2 (arom.
C, CˆN); 67.9, 66.9 (2d, CHCl
2
); 42.9, 42.7 (2t, CH
2
Cl of 7b and 7a); 17.7, 16.7 (2q, Me of 6a and 6b).
1
N-[4-Chloro-2-(chloromethyl)phenyl]benzimidoyl Chloride (7b): H-NMR: 8.17 ± 6.89 (m, 8arom. H);
1
3
4
1
.44 (s, CH
7.7 (q, Me of 6b).
. Preparation of 4-Amino-2-phenyl-6H-[5,1,3]benzodiazocines. General Procedure. A freshly prepared
soln. of 1.1 equiv. of KSeCN in dry acetone was added to a stirred soln. of 7 in dry acetone at À 58 to 08. The
stirring was continued at 08 for 1 h, and the solvent was removed i.v. CHCl was added to the residue, the
2
Cl); 2.11 (s, Me of 6b). C-NMR: 145.7 ± 121.6 (arom. C, CˆN); 66.9 (d, CHCl
2 2
); 42.0 (t, CH Cl);
4
3
precipitated KCl was removed by filtration, the solvent was removed i.v., and the remaining oily
isoselenocyanate 8 was used without additional purification. When 0.9 equiv. of the corresponding amine were
added slowly (15 min) to a stirred soln. of the crude 8 in acetone at r.t., the yellow color of the soln. changed to
dark brown. The mixture was stirred for another 15 min, while the formation of amine ¥ HCl was observed. This
salt was removed by filtration, and the filtrate was left to stand at r.t. for 24 h. Pale yellow 9 precipitated, the
soln. was decanted, the residue was dissolved in CHCl
3
, 1.5 ± 2 equiv. of (diisopropylamino)methylÀpolystyrol
(
polymer base) were added, and the mixture was stirred for 10 min. The polymer base was filtered, the solvent
was removed i.v., and the remaining oil was dissolved in MeOH. Pale yellow crystals of 10 were formed, which
were recrystallized from MeOH.
4-(Morpholin-4-yl)-2-phenyl-6H-[5,1,3]benzoselenadiazocine (10a). From 1 g (3.78mmol) of 7a and
2
3
1
6
96.4 mg (3.40 mmol) of morpholine: 0.2 g (14.4%). Yellowish crystals. M.p. 120.9 ± 121.98 (MeOH). IR: 3409w,
062w, 3020w, 2957m, 2923w, 2896m, 2847s, 1688w, 1630s, 1587s, 1567s, 1488m, 1478s, 1445s, 1427m, 1367s, 1357s,
1
309m, 1287m, 1275m, 1263s, 1236m, 1202s, 1190s, 1169s, 1139m, 1115s, 1088m, 1058s, 1010s. H-NMR: 8.10 ±
2 2 2
.80 (m, 9 arom. H); 4.50 (d-like, 1 H of CH Se); 3.58± 3.35 ( m, 4 CH of morpholine, 1 H of CH Se).
1
3
C-NMR: 160.1, 148.0, 134.0, 129.9 (4s, 2 CˆN, 3 arom. C); 131.1, 128.6, 128.3, 128.7, 124.0, 121.1 (6d, 9 arom.
‡
CH); 66.2 (t, 2 CH
2
O); 49.0 (t, 2 CH
2
N); 27.2 (t, CH
2
Se). CI-MS: 386 (100, [M ‡ 1] ), 274 (15).
2-Phenyl-4-(pyrrolidin-1-yl)-6H-[5,1,3]benzoselenadiazocine (10b). From 1 g (3.78mmol) of 7a and
2
3
1
3
1
41.8mg (3.40 mmol) of pyrrolidine: 0.1 g (7.5%). Yellowish crystals. M.p. 166.0 ± 167.0 8 (MeOH). IR: 3431w,
060w, 2967w, 2922w, 2862w, 1616s, 1584s, 1564s, 1473m, 1446m, 1421w, 1383s, 1335s, 1276w, 1264s, 1225s, 1186m,
1
168s, 1137m, 1088m, 1052s, 1033m, 1022m. H-NMR: 8.10 ± 6.80 (m, 9 arom. H); 4.55 (d-like, 1 H of CH
2
Se);
1
3
.48± 3.15 ( m, 2 CH
2
N of pyrrolidine, 1 H of CH
2
Se); 1.76 (t-like, 2 CH
2
of pyrrolidine). C-NMR: 159.3, 150.9,
43.6, 136.7, 129.8(5 s, 2 CˆN, 3 arom. C); 130.3, 128.6, 128.4, 128.2, 128.0, 123.3, 121.0 (7d, 9 arom. CH); 49.2
‡
(
t, 2 CH
2
N of pyrrolidine); 27.0 (t, 2 CH
2
of pyrrolidine); 25.0 (t, CH
2
Se). CI-MS: 370 (100, [M ‡ 1] ), 368(55),
3
66 (24). Anal. calc. for C19
-(Benzylamino)-2-phenyl-6H-[5,1,3]benzoselenadiazocine (10c). From 2 g (7.5 mmol) of 7a and 723.3 mg
6.75 mmol) of PhCH NH : 0.7 g (24.1%). Yellowish crystals. M.p. 162.1 ± 163.08 (toluene). IR: 3220m, 3059w,
026w, 2990w, 2937w, 1634s, 1584s, 1563s, 1507s, 1493s, 1477s, 1450m, 1429m, 1359m, 1327s, 1305m, 1277w,
19 3
H N Se (368.33): C 61.96, H 5.20, N 11.41; found: C 61.76, H 5.19, N 11.68.
4
(
2
2
3
1
5
1
1
247m, 1216s, 1172m, 1138w, 1093m, 1067m. H-NMR: 7.97 ± 7.93 (m, 2 arom. H); 7.48± 6.90 ( m, 12 arom. H);
2
.00 (br. s, NH); 4.66 (d, J ˆ 10.5, 1 H of CH
2
Se); 4.53 (dd, J ˆ 15.1, 6.2, 1 H of PhCH
2
); 4.19 (dd, J ˆ 15.1, 4.0,
2
13
H of PhCH
2
); 3.51 (d, J ˆ 10.5, 1 H of CH
2
Se). C-NMR: 160.8, 143.0, 135.8, 137.8, 130.2 (5s, 2 CˆN, 4 arom.
C); 130.7, 128.9, 128.7, 128.5, 128.4, 128.2, 127.2, 123.5, 120.9 (9d, 14 arom. CH); 47.0 (t, PhCH
2
); 27.0 (t, CH
2
Se).
‡
CI-MS: 406 (100, [M ‡ 1] ). Anal. calc. for C22
19 3
H N Se (404.37): C 65.35, H 4.74, N 10.39; found: C 65.09, H
4
.78, N 10.22.
-(Cyclohexylamino)-2-phenyl-6H-[5,1,3]benzoselenadiazocine (10d). From 1 g (3.78mmol) of 7a and
4
3
3
1
37.2 mg (3.40 mmol) of cyclohexylamine: 0.2 g (14.0%). Yellowish crystals. M.p. 135 ± 1368 (toluene). IR:
147m, 3060w, 2928s, 2853s, 1629s, 1583s, 1551s, 1527s, 1478s, 1445s, 1424m, 1356s, 1250m, 1207s, 1180m, 1170m,
1
2
147w. H-NMR: 8.05 ± 8.02 (m, 2 arom. H); 7.48± 6.94 ( m, 7 arom. H); 4.62 (d, J ˆ 10.3, 1 H of CH
2
Se); 4.50
11). C-NMR: 161.1,
41.4, 136.1, 130.6 (4s, 2 CˆN, 3 arom. C); 130.5, 128.7, 128.5, 128.4, 128.2, 123.2, 120.6 (7d, 9 arom. CH); 52.0
1
3
(
6 2 6 6
d-like, NHC H11); 3.52 ± 3.48( m, 1 H of CH Se, 1 H of C H11); 1.94 ± 0.70 (m, 10 H of C H
1

Helvetica Chimica Acta ± Vol. 87 (2004)
1463
‡
(
d, CH of C
calc. for C21
-Chloro-2-phenyl-4-(pyrrolidin-1-yl)-6H-[5,1,3]benzoselenadiazocine (10e). From 1 g (3.35 mmol) of 7b
and 214.4 mg (3.02 mmol) of pyrrolidine: 0.1 g (7.8%). Yellowish crystals. M.p. 176.0 ± 176.18 (MeOH). IR:
6
H
11); 32.3, 31.8, 27.0, 25.5, 24.5, 24.3 (6t, 5 CH
2
of C
6
H
11, CH
2
Se). CI-MS: 398(100, [ M ‡ 1] ). Anal.
23 3
H N Se (396.39): C 63.63, H 5.85, N 10.60; found: 63.61, 5.67, 10.43.
8
3
1
425w, 3058w, 2987w, 2948w, 2865m, 1610s, 1597s, 1581s, 1567s, 1488w, 1466s, 1424m, 1392s, 1332s, 1307m, 1270s,
258m, 1229s, 1181s, 1162s, 1131m, 1099m, 1077m. H-NMR: 8.10 ± 6.80 (m, 8arom. H); 4.50 ( d-like, 1 H of
1
CH
2
Se); 3.56 ± 3.07 (m, 2 CH
2
N of pyrrolidine, 1 H of CH
2 2
Se); 1.79 (t-like, 2 CH of pyrrolidine). CI-MS: 404
‡
(100, [M ‡ 1] ), 402 (50). Anal. calc. for C19
H18ClN
3
Se (402.78): C 56.66, H 4.50, N 10.43; found: C 56.40, H 4.65,
N 10.51.
. Reactions with N-[2-(Chloromethyl)phenyl]benzimidoyl Isothiocyanate (8). A soln. of 7a (1.0 g,
.78mmol) in dry acetone (6 ml) was stirred at 0 8, while a soln. of KSCN (0.39 g, 4 mmol) in dry acetone (20 ml)
was added dropwise. The stirring was continued at 08 for 1 h. The solvent was removed i.v., and CHCl (35 ml)
5
3
3
was added to the residue. The precipitated KCl was removed by filtration, the solvent was evaporated i.v., and
the remaining isothiocyanate 8 was used without further purification. It was dissolved in 25 ml of dry acetone,
morpholine (1.65 g, 5 equiv.) was added at once, and the mixture was stirred for 15 min at r.t. Then, the reaction
was quenched with H
2
O, the mixture was extracted with CH
2
Cl
2
(3Â), and the extracts were combined and
evaporated to dryness. The remaining glue was purified by flash chromatography (AcOEt/hexane 1:2.5) and
crystallization from the same solvent mixture. Yield: 0.17 g (10.6%) of 13. Yellowish crystals. M.p. 183.9 ± 184.88
(AcOEt/hexane). IR: 3443w, 3230m, 3060w, 2971m, 2949s, 2907s, 2875s, 2843s, 2826s, 1675s, 1587s, 1576s, 1530s,
1
1
494m, 1474s, 1453s, 1427s, 1362m, 1346s, 1315s, 1298s, 1287s, 1259s, 1239s, 1222s, 1208s, 1180m, 1157w, 1114s,
1
081s, 1069m, 1044w, 1027s, 1005s. H-NMR: 10.88 (s, NH); 7.90 ± 6.80 (m, 9 arom. H); 4.13 (t-like, CH
2
O); 3.89
(
2
1
(
6
t-like, CH
.36 (t-like, 2 CH
2
O); 3.69 (t-like, CH
2
O); 3.64 (t-like, CH
2
O); 3.62 (t-like, CH
2
N); 3.55 ± 3.51 (m, CH
2
N, CH Ar);
2
1
3
2
N). C-NMR: 188.8 (s, CS); 155.9, 139.4, 135.2, 126.4 (4s, CˆN, 3 arom. C); 130.8, 130.2,
28.4, 128.1, 123.6, 122.0 (6d, 9 arom. CH); 66.6, 66.3, 62.0 (3t, 4 CH
2
O); 53.0, 48.6 (2t, 4 CH
2
N); 47.8
‡
t, ArCH
2
). ESI-MS: 425 (70, [M ‡ 1] ), 338( 84 ), 279 (100). Anal. calc. for C 23
28 4 2
H N O
S (424.56): C 65.07, H
.65, N 13.20; found: C 65.07, H 6.82, N 13.07.
-(Morpholin-4-yl)-2-phenyl-6H-[5,1,3]benzothiadiazocine (12). From 1 g (3.78mmol) of 7a and 296.4 mg
3.40 mmol) of morpholine: 0.3 g (24.6%). Yellowish crystals. M.p. 136 ± 1378 (MeOH). IR: 3424w, 3059w,
4
(
3
1
025w, 2984w, 2971m, 2956w, 2931w, 2913w, 2890w, 2855m, 2843m, 1622s, 1587s, 1564s, 1477s, 1448s, 1362s, 1352s,
301m, 1288m, 1265s, 1251m, 1236m, 1198s, 1184s, 1169s, 1122s, 1096s, 1060s, 1032s, 1024m, 1033s. H-NMR
1
(
(D
m, 4 CH
29.1, 128.5, 128.2, 127.7, 123.4, 120.6 (7d, 9 arom. CH); 65.5 (t, 2 CH
6
)DMSO): 8.10 ± 6.80 (m, 9 arom. H); 4.22 (d-like, 1 H of CH
2
S); 3.78( d-like, 1 H of CH
)DMSO): 158.6, 151.6, 150.9, 135.9, 127.4 (5s, 2 CˆN, 3 arom. C); 130.6,
O); 47.3 (t, 2 CH N); 31.9 (t, CH S). CI-
2
S); 3.45 (narrow
1
3
2
of morpholine). C-NMR (D
6
1
2
2
2
‡
MS: 338(100, [ M ‡ 1] ), 226 (8).
6. Preparation of Diethyl 2-(1H,6H-[5,1,3]Benzoselenadiazocin-4-ylidene)propanedioates. To a soln. of
EtONa, prepared from Na (0.1 g, 4.34 mmol) and abs. EtOH (3 ml), 0.7 g (4.37 mmol) of diethyl propanedioate
was added. The mixture was stirred at r.t. until the Na was completely dissolved. Then, the oily isoselenocyanate
8
and additional abs. EtOH (20 ml) was added, providing an orange-yellow-colored mixture. A small amount of
CH Cl was added to dissolve 8 completely, and the mixture was stirred at r.t. for 24 h. The solvent was removed
i.v., CHCl was added to the residue, and the precipitated NaCl was removed by filtration. The solvent was
2
2
3
removed i.v., the remaining oil was dissolved in MeOH, and yellow crystals of 14 were formed.
Diethyl 2-(2-Phenyl-1H,6H-[5,1,3]benzoselenadiazocin-4-ylidene)propanedioate (14a). From 1.0 g
(
3.78mmol) of 7a: 0.5 g (27.5%).Yellowish crystals. M.p. 179.4 ± 180.48 (MeOH). IR: 3287m, 3119w, 3059w,
2
1
979w, 2940w, 1711s, 1634s, 1601s, 1585s, 1540s, 1447m, 1431m, 1385w, 1363m, 1330s, 1273s, 1242s, 1187s, 1095s,
1
054s, 1027m. H-NMR ((D
6
)DMSO): 9.61 (s, NH); 8.00 ± 6.90 (m, 9 arom. H); 4.15 ± 3.75 (m, 3 CH
)DMSO): 156.9 (s, 2 CO); 147.6, 135.4, 134.8, 134.7 (4s, 3 C, 3 arom. C); 131.2,
30.2, 128.6, 128.2, 126.7, 126.2, 123.2 (7d, 9 arom. CH); 59.6 (t, 2 CH O); 25.3 (t, CH Se); 13.9 (q, 2 Me). CI-
Se (457.38): C 57.77, H 4.85, N 6.12; found: C 57.51, H 4.78, N
2
); 1.09
1
3
(
1
t, J ˆ 7.1, 2 Me ) . C-NMR ((D
6
2
2
‡
MS: 459 (100, [M ‡ 1] ). Anal. calc. for C22
.08.
Diethyl 2-(8-Chloro-2-phenyl-1H,6H-[5,1,3]benzoselenadiazocin-4-ylidene)propanedioate (14b). From
.0 g (3.35 mmol) of 7b: 0.3 g (17.5%). Yellowish crystals. M.p. 192.5 ± 193.58 (MeCN). IR: 3295s, 3109w,
22 2 4
H N O
6
1
3
1
056w, 2979m, 2942w, 2905w, 2870w, 1709s, 1636s, 1596m, 1583m, 1533s, 1488s, 1448m, 1429m, 1394w, 1385w,
1
364s, 1332s, 1275s, 1242s, 1183s, 1095s, 1071m, 1047s, 1028s. H-NMR ((D
6
)DMSO): 9.78( s, NH); 7.83 ± 7.15
)DMSO): 156.4 (s, CO); 147.7,
1
3
(
m, 8arom. H); 4.03 ± 3.95 ( m, 3 CH
2
); 1.09 (t, J ˆ 7.1, 2 Me ) . C-NMR ((D
6
1
37.6, 134.6, 133.8, 129.5, 109.3 (6s, 3 C, 4 arom. C); 131.3, 129.5, 128.7, 128.2, 126.7, 125.0 (6d, 8arom. CH); 59.8
‡
(
t, 2 CH
2
O); 24.9 (t, CH
2
Se); 13.8( q, 2 Me). CI-MS: 493 (100, [M ‡ 1] ), 491 (55).

Table 2. Crystallographic Data of 10a, 10c, 10d, 12, and 14a
1
0a
10c
10d12
14a
MeOH
Crystallized from
MeOH
MeOH
MeOH
benzene
Empirical formula
Formula weight [g mol
Crystal color, habit
Crystal dimensions [mm]
Temp. [K]
C
19
H
18.94Cl0.06
N
3
OSe ¥ CH
3
OH
C
404.31
colorless, needle
0.05 Â 0.10 Â 0.20
160(1)
22
H
19
N
3
Se
C
396.33
pale yellow, plate
0.07 Â 0.17 Â 0.20
160(1)
21
H
23
N
3
Se
C
19
H
18.96Cl0.04
N
3
OS
22 2 4
C H21.96Cl0.04N O Se
458.67
colorless, needle
0.10 Â 0.12 Â 0.30
160(1)
À1
]
419.39
colorless, prism
338.92
colorless, prism
0.15 Â 0.25 Â 0.30
0.08 Â 0.12 Â 0.22
273(1)
160(1)
Crystal system
Space group
triclinic
P1
monoclinic
monoclinic
monoclinic
monoclinic
P2 /c
1
≈
P2
1
/c
P2
1
/c
P2
1
/c
Z
2
4
4
4
4
Reflections for cell determination
19631
4 ±60
430
5976838
4 ±60
3909
34266
2
q Range for cell determination [8]
4 ±60
2 ±55
2 ±60
Unit-cell parameters a [ä]
8.8121(1)
10.5147(1)
11.2697(1)
80.8246(6)
71.8921(6)
79.0644(5)
968.81(2)
1.434
7.2795(1)
23.9734(3)
10.3480(1)
90
92.1258(5)
90
1804.63(4)
1.488
2.090
16.1257(2)
8.6671(1)
13.3571(1)
90
91.4886(5)
90
1866.20(3)
1.411
2.019
8.5473(1)
22.8421(4)
9.1539(1)
90
110.9784(9)
90
1668.73(4)
1.349
0.212
15.8889(2)
8.4845(1)
15.7701(2)
90
106.6631(7)
90
2036.68(4)
1.496
1.879
b [ä]
c [ä]
a [8]
b [8]
g [8]
3
V [ä ]
À3
D
x
[g cm
m(MoK ) [mm
Scan type
]
À1
a
]
1.964
f and w
60
f and w
60
f and w
60
f and w
55
f and w
60
2q(max) [8]
Transmission factors (min; max)
Total reflections measured
Symmetry independent reflections
Reflections used [I > 2s(I)]
Parameters refined
0.608; 0.759
31912
5637
5084
249
0.687; 0.881
42906
5275
4346
239
0.638; 0.833
55731
54483799
4675
±
0.645; 0.823
54315
37406
5952
2713
4608
276
230
227
Final R
0.0297
0.0319
0.005
0.04780.0296
0.0491
0.005
3.047
±
0.0006
1.83; À 0.91
0.0425
0.0322
0.005
2.297
±
0.001
0.46; À 0.52
0.0369
wR
0.0415
0.01
2.006
0.0378
0.01
2
2 À1
Weights: p in w ˆ [s (F
O
) ‡ (pF
O
) ]
Goodness-of-fit
2.142
1.860
À6
À7
À7
Secondary extinction coefficient
Final Dmax/s
D1 (max; min) [e ä
1.1(2) Â 10
7(2) Â 10
2.6(8) Â 10
0.001
0.0004
0.0008
À3
]
0.34; À 0.45
0.31; À 0.27
0.44; À 0.54

Helvetica Chimica Acta ± Vol. 87 (2004)
1465
3
7
. X-Ray Crystal-Structure Determination of 10a, 10c, 10d, 12, and 14a (see Table 2 and Figs. 1 ± 4) ). All
measurements were performed at 160 K (273 K in the case of 10a) on a Nonius Kappa CCD diffractometer [20]
with graphite-monochromated MoK radiation (l 0.71073 ä) and an Oxford Cryosystems Cryostream 700
a
cooler. The data collection and refinement parameters are given in Table 2, and views of the molecules are
shown in Figs. 1 ± 4. Data reduction was performed with HKL Denzo and Scalepack [21]. The intensities were
corrected for Lorentz and polarization effects, and a numerical absorption correction [22] was applied in the
cases of 10a, 10c, 10d, and 14a. Each structure was solved by direct methods with SIR92 [23], which revealed the
positions of all non-H-atoms.
After the initial structural model for 10a, 12, and 14a had been refined, a residual electron-density peak of
À3
1
.9, 0.9, and 1.4 e A , respectively, remained ca. 1.6 ä from C(9) of the phenyl ring. Given the chemical
evidence, which suggests this peak could be due to the presence of a small amount of a Cl-substituted derivative,
a low-occupancy Cl-atom was defined at the site of the residual peak and the R factors subsequently improved
significantly. Refinement of the site-occupation factor yielded a value of 0.060(2), 0.043(2), and 0.039(2),
respectively, while the anisotropic atomic-displacement parameters remained reasonable. Thus, it is assumed
that a Cl-substituent exists at C(9) in ca. 6, 4, and 4%, respectively, of the molecules in the crystals, so that the
crystals are mixtures of two compounds sharing the same position in the unit cell, hence having the appearance
of disorder, and this assumption was employed in defining the final refinement model. The geometry involving
the C(9)ÀCl(9) bond is quite poor in each structure, for example C(9)ÀCl(1) in 10a is 1.57 ä instead of the
usual 1.76 ä, but this is not surprising given that the low site occupation of the Cl-atom results in low precision
for the position of this atom, and the fact that, in the model, this Cl-atom is disordered and partially overlapping
with the H-atom at C(9) in the unsubstituted major component. In the case of 10a, the asymmetric unit also
contains one molecule of MeOH.
For 10c, after the structural model corresponding to the expected molecule had been defined and refined
À3
fully, one peak of residual electron density of 1.8e ä also remained. This peak is positioned over the outer end
of the benzyl ring, but to the side of the ring. The peak is 1.24, 0.92, and 1.61 ä from atoms C(8), C(9), and
C(10), respectively. This peak cannot be reconciled with any obvious chemical explanation as it is not possible
for a substituent on the ring to adopt this position, so the peak was ignored in the final refinement. The next
À3
highest residual peak was only 0.65 e ä . A second data collection with a fresh crystal gave an identical result,
À3
although the peak represented a slightly smaller residual electron density of 1.3 e ä
.
In all compounds, the non-H-atoms were refined anisotropically. The OH H-atoms of MeOH in 10a and the
amine H-atoms in 10c, 10d, and 14a were placed in the positions indicated by difference-electron-density maps,
and their positions were allowed to refine together with an isotropic displacement parameter. All other H-atoms
in the structures were fixed in geometrically calculated positions, and each was assigned a fixed isotropic
displacement parameter with a value equal to 1.2 Ueq of its parent C-atom. Refinement of the structures was
carried out on F according to full-matrix least-squares procedures, which minimized the function Sw(j F
O
jÀ
2
j F
C
j ) . A correction for secondary extinction was applied in the cases of 10a, 12, and 14a. Three, three, and
one reflections, whose intensities were considered to be extreme outliers, were omitted from the final
refinement of 10c, 12, and 14a, respectively. Neutral atom scattering factors for non-H-atoms were taken from
[24a], and the scattering factors for H-atoms were taken from [25]. Anomalous dispersion effects were included
in F [26]; the values for f' and f'' were those of [24b]. The values of the mass attenuation coefficients are those
c
of [24c]. All calculations were performed with the teXsan crystallographic software package [27].
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Received January 30, 2004