Synthesis and Chemistry of Benzo[ e][1,2,6]thiadiazino[3,4- b][1,4]diazepin-10(11 H)-ones and Related Ring Transformations

Article abstract of DOI:10.1021/acs.joc.1c00206

2-[(3,5-Dichloro-4H-1,2,6-thiadiazin-4-ylidene)amino]benzamides are cyclized to benzo[e][1,2,6]thiadiazino[3,4-b][1,4]diazepin-10(11H)-ones via (i) treatment with NaH and via (ii) Pd-catalyzed C-N coupling. The behavior of the latter toward nucleophiles a

Full text of DOI:10.1021/acs.joc.1c00206

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Article
Synthesis and Chemistry of
Benzo[e][1,2,6]thiadiazino[3,4‑b][1,4]diazepin-10(11H)‑ones and
Related Ring Transformations
Andreas S. Kalogirou,* Andreas Kourtellaris, and Panayiotis A. Koutentis*
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ABSTRACT: 2-[(3,5-Dichloro-4H-1,2,6-thiadiazin-4-ylidene)-
amino]benzamides are cyclized to benzo[e][1,2,6]thiadiazino[3,4-
b][1,4]diazepin-10(11H)-ones via (i) treatment with NaH and via
(ii) Pd-catalyzed C-N coupling. The behavior of the latter toward
nucleophiles and thermal, oxidative, and reductive conditions
revealed unexpected transformations to 3,5-dioxo-4,5-dihydro-3H-
benzo[e][1,4]diazepine-2-carbonitrile and 2-(4-substituted-1,2,5-
thiadiazol-3-yl)quinazolin-4(3H)-ones.
Scheme 1. Conversion of Tetrachlorothiadiazine 3 to
Diazepines 2 and 4
INTRODUCTION
■
Benzo[e][1,4]diazepines and their hetareno-fused analogues
can act as allosteric enhancers of the binding of the
neurotransmitter gamma-amino butyric acid (GABA) in the
neuronal GABAA receptors.1 This behavior has led to uses in
pharmaceuticals, in particular, as psychoactive drugs with
anxiolytic, sedative, and hypnotic activity, e.g., commercial 1,4-
benzodiazepine drugs include diazepam (anxiolytic) and
flumazenil (benzodiazepine overdose antidote)2 (Figure 1).
rare, but have uses in both the biological8,9 and materials
sciences.10,11 Their chemistry and applications have recently
been reviewed.12 Our interest in thiadiazines is currently
focused on 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (3), which
can be prepared from dichloromalononitrile and SCl2,13 or
from N-2,2-trichloro-2-cyanoacetimidoyl chloride and S8.14
Thiadiazine 3 is used to synthesize aromatic 1,2,6-thiadiazines
such as 2-(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)-
malononitrile (5),15 N-aryl-3,5-dichloro-4H-1,2,6-thiadiazin-4-
imines 6,16 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (7),15 and
3,5-dichloro-4H-1,2,6-thiadiazin-4-thione (8).17 Furthermore,
it can be used to prepare C(4)-saturated analogues such as 4,4-
diamino-,18 4,4-dialkoxy-, and 4,4-bis(alkylthio)-3,5-dichloro-
4H-1,2,6-thiadiazines 9, 10, and 11, respectively17 (Scheme 2).
Figure 1. Examples of benzo[e][1,4]diazepines.
Di(het)areno[b,e][1,4]diazepin-11-ones, e.g., compound 1
(Figure 1), are a less explored structural sub-category that act
as anticancer agents,3 HIV non-nucleoside reverse transcriptase
inhibitors,4 and antiarrhythmic agents.5 Changing the site of
the (het)areno fusion can change the biological activity of the
system; i.e., novel hetero-[b]-fused benzo[e][1,4]diazepines
can therefore lead to new applications.
Recently, the thiadiazino-fused diazepine 2, a previously
unknown ring system, was isolated in low yield (3%) from the
chloride-mediated thermal degradation of tetrachlorothiadia-
zine 3 (Scheme 1).6 Intrigued by its formation and our interest
in discovering new 1,2,6-thiadiazine chemistry and applica-
tions, we targeted the synthesis of analogous benzo-fused
systems 4 (Scheme 1).
Received: January 27, 2021
Published: April 5, 2021
1,2,6-Thiadiazines are sulfur-nitrogen heterocycles that have
broad applications.7 Non S-oxidized 4H-1,2,6-thiadiazines are
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14 (Scheme 3).18 An alternative cyclization of benzamides 13
at the thiadiazine C(3/5) position could give the desired
thiadiazino-fused benzodiazepines 4, which are structural
analogues to the thiadiazino-fused thiazolodiazepine 2
(Scheme 1). Herein, we present the formation of benzothia-
diazinodiazepines 4, via the cyclization of benzamides 13, and
related chemistry. Other routes to diazepines 4 were also
investigated, but with no success [see Supporting Information
(SI)].
Scheme 2. Selected Transformations of
Tetrachlorothiadiazine 3
Carboxamide 13a (R = H) can be prepared in two steps
from tetrachlorothiadiazine 3.18 Prior stability studies on
amide 13a revealed that acidic conditions, protic solvents, and
thermal conditions induce its conversion to spirocycle 12a.18
An investigation of its reactivity showed that cyclization on the
thiadiazine C(3) position occurred under basic conditions or
in the presence of Pd catalysts (see SI for details). Two sets of
conditions were promising: the first being treatment with NaH
(1 equiv), in THF, at ca. 20 °C, for 15 min that gave a deep
orange-colored diazepine 4a (68%), together with a small
amount of the known colorless spirocycle 12a (2%) (Table 1);
the structure of diazepine 4a was supported by single crystal X-
ray studies (Figure 2). For structure elucidation details, see the
RESULTS AND DISCUSSION
■
Recently, we described the 3-step synthesis of 3′,5′-dichloro-
1H-spiro(quinazoline-2,4′-[1,2,6]thiadiazin)-4(3H)-ones 12
starting from tetrachlorothiadiazine 3 (Scheme 3).18 The
Scheme 3. Reactions of Benzamides 13
Figure 2. X-ray structure of 4-chlorobenzo[e][1,2,6]thiadiazino[3,4-
b][1,4]diazepin-10(11H)-one (4a) (CCDC-2052542).
cyclization of benzamides 13 on the thiadiazine C(4) position
to give spirocycles 12 was enabled by protic solvents and heat.
Spirocycle 12 (R = H) can also be decomposed to quinazoline
SI. The second set of conditions involved Superstable Pd(0)
(1.25 mol %), DPEphos (0.05 equiv), K2CO3 (1.5 equiv), in
Table 1. Conversion of Thiadiazinimines 13a−j to Diazepines 4a−j and Spirocycles 12a−j
conditions A
conditions B
entry
13 (R)
time (h) yield 4 (%) yield 12 (%) total (4+12) (%) entry time (h) yield 4 (%) yield 12 (%) total (4+12) (%)
1
2
3
4
5
6
7
8
9
13a (H)
0.25
0.25
0.25
24
0.25
0.75
0.50
0.16
0.16
4
68
32
41
46
44
62
65
60
69
20
2
10
30
0
42
31
33
36
28
24
70
42
71
46
86
93
98
96
97
44
11
12
13
14
15
16
17
18
19
20
24
96
30
72
24
12
48
24
24
48
76
32
66
67
57
74
67
56
62
65
13
20
19
9
34
21
19
33
31
28
89
52
85
76
91
95
87
89
93
93
13b (4-Me)
13c (5-Me)
13d (6-Me)
13e (4-Cl)
13f (5-Cl)
13g (6-Cl)
13h (4-Br)
13i (5-Br)
13j (6-Br)
10
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THF, at ca. 20 °C, for 24 h that gave products 4a and 12a in
76% and 13% yields, respectively.
After briefly investigating the reaction scope, we assessed the
chemistry of the parent diazepine 4a starting from the
substitution of the C(4) chloride. Nucleophilic displacements
with N-, O-, and S-nucleophiles were initially studied.
Treatment of diazepine 4a with pyrrolidine (2 equiv) in
THF at ca. 20 °C for 3 h gave 4-(pyrrolidin-1-yl)benzo[e]-
[1,2,6]thiadiazino[3,4-b][1,4]diazepin-10(11H)-one (15) in
89% yield (Scheme 5). Reaction with MeONa (2 equiv), in
Mechanistically, the formation of diazepine 4a is attributed
to a 7-endo-trig cyclization reaction, while the intriguing
formation of spirocycle 12a can be attributed to a competing
6-endo-trig cyclization. Both cyclizations are allowed according
to Baldwin’s rules.19 Prior studies support that the formation of
spirocycles 12 does not require the deprotonation of starting
benzamides as they can be exclusively formed in the absence of
base.18 Despite considerable effort, we failed to prevent their
formation during the synthesis of the diazepines 4.
Scheme 5. Chloride Displacement of Diazepine 4a
The possibility that spirocycles 12 were precursors to
diazepines 4 was investigated. Treatment of spirocycle 12a
with NaH (1 equiv) in THF at ca. 20 °C led to a slow
consumption of the starting material 12a (24 h) and isolation
of diazepine 4a in 21% yield; no other products were observed.
Performing the reaction at ca. 66 °C led to a faster
consumption of the spirocycle 12a (1 h) and a slightly
improved yield of diazepine 4a (31%) (Scheme 4).
Scheme 4. Investigation of the Conversion of Spirocycle 12a
into Diazepine 4a
MeOH, at ca. 20 °C gave only unreacted starting material, and
heating to ca. 65 °C led to a complex mixture of products
(TLC), while similar results were also obtained with PhONa.
This can potentially be attributed to the acidity of the amide
proton of diazepine 4a that leads to deprotonation in the
presence of stronger bases like alkoxides. The deprotonated
anion of 4a was expected to be less reactive due to the electron
donation of the anionic nitrogen into the thiadiazine ring.
Treatment of diazepine 4a with PhSH (2 equiv) and Et3N (2
equiv), in THF, at ca. 20 °C for 6 h led to its complete
consumption and formation of phenylsulfide 16 in 82% yield
(Scheme 5).
Furthermore, some Pd coupling reactions on the C(4)
position were investigated. Stille coupling of diazepine 4a with
PhSnBu3 (1.1 equiv), in PhMe, in the presence of Pd-
(Ph3P)2Cl2 (5 mol %), at ca. 110 °C, gave the 4-phenyl-
thiadiazine 17 in a moderate 64% yield (Scheme 5).
Unfortunately, Suzuki couplings were not as effective;
PhB(OH)2 (1.5 equiv), in dioxane/H2O (5:3), in the presence
of Na2CO3 (1 equiv) and Pd(Ph3P)4 (5 mol %), at ca. 100 °C
gave product 17 in only 4% yield. Alternative anhydrous
conditions involving PhB(OH)2 (1.5 equiv), KF (1.7 equiv),
18-crown-6 (0.5 equiv), Pd(OAc)2 (5 mol %), in PhMe, at ca.
110 °C,22 led to degradation of the starting material.
Tentatively, the formation of spirocycle 12a was thermody-
namically favored, and a higher activation energy is required to
ring open the spirocycle 12a than that needed for the
cyclization of the starting benzamide 13a to give the diazepine
4a.
The reaction scope was then investigated (Table 1) by
screening the above two sets of conditions with the known
benzamides 13b−j.18 The three electron releasing methyl-
substituted analogues 13b−d gave moderate yields of
diazepines 4b−d (32−67%) with 5-methylbenzamide 13c
giving the higher overall yield (71% and 85%) with both sets of
conditions (Table 1, entries 3 and 13). The use of conditions B
improved the yields of diazepine in both the 5- and the 6-Me
analogues, but no improvement was observed with the 4-Me
analogue. Chloro-substituted analogues 13e−g gave moderate
yields (44−74%) of diazepines 4e−g along with 31−42% of
spirocycles 12e−g, totaling to an almost quantitative
conversion (Table 1, entries 5−7 and 15−17).
Conditions B gave marginally better yields of diazepines 4e−
g compared to conditions A. Similar results to the chloro-
substituted analogues were obtained with 4- and 5-bromo
analogues 13h and 13i, respectively. The 6-bromo analogue
13j, however, gave a significantly lower yield (Table 1, entries
8−10 and 18−20), presumably owing to steric effects as the
group next to the nucleophilic amide can hinder its ability to
attack the thiadiazine C(3) position. Moreover, for 6-
substituted analogues, in the case of the large Me (AMe 1.70
kcal/mol),20 and Br groups (ABr 0.49 kcal/mol),21 prolonged
reaction times were observed, but not with the large Cl group
(ACl 0.51 kcal/mol).21
Nitration of the peripheral arene ring of diazepine 4a was
also attempted to further diversify the functionality of the
tricyclic ring system. Pleasingly, treatment of diazepine 4a with
KNO3 (1 equiv) in concd H2SO4, at ca. 0 °C led to rapid
consumption of the starting material and isolation of 4-chloro-
8-nitrobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]diazepin-10-
(11H)-one (4k) (see SI for structure elucidation) in 93% yield
(Scheme 6).
Subsequently, we studied the methylation of the N(11)
atom of the diazepine 4a. Reaction with MeI (4 equiv), after
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Scheme 6. Nitration of Diazepine 4a
Figure 3. X-ray structure of 2-amino-N-(5-chloro-4-oxo-4H-1,2,6-
thiadiazin-3-yl)benzamide (19) (CCDC-2052543).
treatment with NaH (2 equiv), in THF, at ca. 0 °C gave a high
92% yield of 4-chloro-11-methylbenzo[e][1,2,6]thiadiazino-
[3,4-b][1,4]diazepin-10(11H)-one (18) (Scheme 7). The site
Surprisingly, heating a solution of diazepine 4a in AcOH, at
ca. 117 °C, for 3 h led to complete consumption of the starting
material and isolation of two unexpected products: the
colorless 2-(4-chloro-1,2,5-thiadiazol-3-yl)quinazolin-4(3H)-
one (20a) and the pink-colored 4-hydroxybenzo[e][1,2,6]-
thiadiazino[3,4-b][1,4]diazepin-10(11H)-one (21) in 43% and
30% yields, respectively (Scheme 9). The structure elucida-
Scheme 7. N-Methylation of Diazepine 4a
Scheme 9. Conversion of Diazepines 4 into Thiadiazoles 20
and Thiadiazinol 21
1
of methylation is supported by the similarity of the H NMR
spectra and of the UV−vis absorptions of 4a (λmax 433 nm, log
ε 4.05) vs 18 (λmax 400 nm, log ε 4.09). Further support was
provided by the 13C NMR spectra, with a δC 166.9 for the
carbonyl signal remaining typical of a carboxamide, while the
δC 36.4 of the methyl supported its attachment to nitrogen.
Interestingly, earlier efforts to prepare N-Me diazepine 18 from
tetrachlorothiadiazine 3 and 2-amino-N-methylbenzamide gave
only 3′,5′-dichloro-3-methyl-1H-spiro[quinazoline-2,4′-
[1,2,6]thiadiazin]-4(3H)-one.23
The potential for selective ring degradations of the parent
diazepine 4a was then investigated. DSC studies of recrystal-
lized diazepine 4a showed a mp at 218.7 °C (onset), followed
by a decomposition at 251.7 °C (onset), to give polar
intractable material (baseline by TLC). In solution, diazepine
4a was stable to mild thermal (PhCl, ca. 132 °C, 4 d) and basic
conditions (Et3N 5 equiv, THF, ca. 20 °C, 4 d). Treatment of
diazepine 4a with glacial AcOH, at ca. 20 °C, for 48 h led to no
reaction, but treatment with 6 M HCl in THF, at ca. 20 °C, led
to a rapid consumption (0.5 h) and formation of colorless 2-
amino-N-(5-chloro-4-oxo-4H-1,2,6-thiadiazin-3-yl)benzamide
(19) in 95% yield (Scheme 8), the structure of which was
tions of both products were supported by single crystal X-ray
analysis (see SI). Worthy of note was that, during an attempted
sublimation of thiadiazinol 21 under a static vacuum of 15
mbar at 250 °C, it decomposed to give only 4-oxo-3,4-
dihydroquinazoline-2-carboxamide (22) (see SI). The for-
mation of thiadiazole 20a was optimized to a 92% yield by use
of MeOH/AcOH (90:10) at ca. 65 °C for 24 h (see SI). The
scope of the reaction was also briefly investigated using the
optimized reaction conditions. Methyl-, chloro-, and bromo-
substituted diazepines 4c, 4f, and 4h were converted to
thiadiazoles 20b−d in good yields (Scheme 9). Methyl-
substituted diazepine 4c gave a 93% yield of thiadiazole 20b,
while the bromo analogue 4h gave a 75% yield of 20d.
Interestingly, the chloro analogue 4f gave a 68% yield of
thiadiazole 20c, albeit with a prolonged reaction time of 6 d,
presumably due to the more electron withdrawing chloride
slowing down the reaction. Attempts to convert the 8-nitro
analogue 4k led only to unreacted starting material. Never-
theless, the 4-phenyldiazepine 17 was successfully converted
into the phenylthiadiazole 20e in 73% yield, demonstrating
that the ring transformation was not limited to 4-chloro-
substituted analogues.
Scheme 8. Acid Hydrolysis of Diazepine 4a
supported by X-ray crystallography (Figure 3). Presumably,
benzamide 19 forms via the acid-catalyzed hydrolysis of the
diazepine C(4a)N(5) imine bond. Benzamide 19 can be
cyclodehydrated to reform the diazepine 4a in 69% yield using
TsOH·H2O (1 equiv) in hot PhH under Dean−Stark
conditions (Scheme 8).
Ring transformations of 1,2,6-thiadiazines into 1,2,5-
thiadiazoles are rare with only one example reported for
some C(4) saturated systems which was mediated by heat and
by Brønsted or Lewis acid catalysis.24 Tentatively, we propose
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that the mechanism of the formation of thiadiazole 20a
proceeds via an initial protonation of the thiadiazine N(1), as
the more basic amidine-like nitrogen site, to give the cationic
thiadiazinium 23, which is then strongly activated to trap an
incoming nucleophile (ROH, where R = H, Me, or Ac) at
C(11a) to give adduct 24. A subsequent 1,2-migration of the
RO group to the C(4a) position establishes an intermediate 25
that is set up to undergo two consecutive Wagner−Meerwein
shifts to give intermediates 26 and then 27, in an analogous
manner to that previously reported for the ring contraction of
thiadiazine ketals.24 A final elimination of the nucleophile gives
the final thiadiazole 20a (Scheme 10).
Scheme 11. Reaction of Diazepine 4a with PIFA
Scheme 10. Proposed Mechanism for the Formation of
Thiadiazole 20a
Figure 4. X-ray structure of 3,5-dioxo-4,5-dihydro-3H-benzo[e][1,4]-
diazepine-2-carbonitrile (28) (CCDC-2052547).
CONCLUSIONS
■
In conclusion, we report the first synthesis of benzo[e]-
[1,2,6]thiadiazino[3,4-b][1,4]diazepin-10(11H)-ones 4 start-
ing from 2-[(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)-
amino]benzamides 13 via two different reactions, treatment
with NaH and Pd-catalyzed C-N coupling. Preliminary
investigations of the reactivity of diazepine 4a revealed the
mechanistically intriguing ring contraction to quinazoline-
thiadiazole 20a and the PIFA-mediated oxidative degradation
of the thiadiazine ring to benzodiazepine 28.
EXPERIMENTAL SECTION
■
General Methods and Materials. All chemicals were commer-
cially available except those whose synthesis is described. Anhydrous
Na2SO4 was used for drying organic extracts, and all volatiles were
removed under reduced pressure. Toluene, acetonitrile, and THF
were distilled over CaH2 before use. Thiophenol was distilled before
use. Reactions were protected from moisture with CaCl2 drying tubes
or an Ar atmosphere. All reaction mixtures and column eluents were
monitored by TLC using commercial glass backed thin layer
chromatography (TLC) plates (Merck Kieselgel 60 F254). The plates
were observed under UV light at 254 and 365 nm. The technique of
dry flash chromatography was used throughout for all non-TLC scale
chromatographic separations using Merck Silica Gel 60 (less than
0.063 mm).27 Melting points were determined using a PolyTherm-A,
Wagner & Munz, Koefler - Hotstage Microscope apparatus or were
determined using a TA Instruments DSC Q1000 with samples
hermetically sealed in aluminum pans under an argon atmosphere,
using heating rates of 5 °C/min (DSC mp listed by onset and peak
values). Solvents used for recrystallization are indicated after the
melting point. UV spectra were obtained using a PerkinElmer
Lambda-25 UV/vis spectrophotometer, and inflections are identified
by the abbreviation “inf”. IR spectra were recorded on a Shimadzu
FTIR-NIR Prestige-21 spectrometer with a Pike Miracle Ge ATR
accessory, and strong, medium, and weak peaks are represented by s,
m, and w, respectively. 1H and 13C NMR spectra were recorded on a
Bruker Avance 300 (at 300 and 75 MHz, respectively), or a 500
machine (at 500 and 125 MHz, respectively). Deuterated solvents
were used for homonuclear lock, and the signals are referenced to the
deuterated solvent peaks. APT NMR studies identified quaternary and
tertiary carbons, which are indicated by (s) and (d) notations,
respectively. MALDI-TOF mass spectra were recorded on a Bruker
Autoflex III Smartbeam instrument, while ESI-APCI+ mass spectra
were recorded on a Model 6110 Quadrupole MSD, Agilent
Worthy of note is that a similar migration of methylthio
groups was reported during the isomerization of trimethyl α-
keto trithioorthocarboxylates into α,α-bis(methylthio) thio-
lcarboxylates.25 Similar ring contractions of benzodiazepines to
quinazolines have been reported,26 but this is the only example
where this rearrangement occurs on a 1,2,6-thiadiazine bearing
a delicate imidoyl chloride moiety.
The stability of diazepine 4a to reductive and oxidative
conditions was also tested. Reaction of diazepine 4a either with
NaBH4 (2 equiv), in MeOH, at ca. 20 °C for 3 d, or with Zn or
Sn (2 equiv), in AcOH, at ca. 20 °C for 24 h, led to complete
consumption of the starting compound but gave only
intractable complex reaction mixtures (TLC). Treatment of
diazepine 4a with MnO2 (10 equiv) in DCM, at ca. 20 °C, for
24 h led to no reaction, whereas reaction with MCPBA (2
equiv), in DCM, at ca. 20 °C led to a complex mixture of
products. However, treatment of diazepine 4a with PIFA (2
equiv), in MeCN, at ca. 20 °C, for 30 min led to complete
consumption of the starting material and isolation of colorless
3,5-dioxo-4,5-dihydro-3H-benzo[e][1,4]diazepine-2-carboni-
trile (28) in 59% yield (Scheme 11), the structure of which
was supported by X-ray crystallography (Figure 4). The
formation of diazepine 28 was attributed to hydrolytic ring
cleavage of an initially formed sulfoxide (see SI for further
details).
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Technologies and ES-API spectra on a Model 1260 Infinity II
Quadrupole MSD, Agilent Technologies. 3,4,4,5-Tetrachloro-4H-
1,2,6-thiadiazine (3),13 2-[(3,5-dichloro-4H-1,2,6-thiadiazin-4-
ylidene)amino]benzamides 13,18 and 2-[(3,5-dichloro-4H-1,2,6-thia-
diazin-4-ylidene)amino]benzonitrile (29)16 were prepared according
to literature procedures.
= 7.7, 7.7, 1.4 Hz), 7.13 (ddd, 1H, J = 7.6, 7.6, 1.0 Hz), 6.71 (ddd,
1H, J = 8.0, 0.5, 0.5 Hz), 3.81 (s, 3H); 13C{1H} NMR (CDCl3, 125
MHz): δ 166.0 (s), 149.8 (s), 134.0 (s), 132.7 (d), 130.7 (d), 123.6
(d), 118.2 (d), 117.2 (s), 52.0 (q), one C (s) resonance missing; m/z
(MALDI-TOF) 318 (MH+ + 2, 77%), 316 (MH+, 100), 286 (34),
284 (56).
Initial Attempts to Access Benzo[e][1,2,6]thiadiazino[3,4-
b][1,4]diazepines 4 (see SI for Discussion Related to
Compounds 29, 30, 33, 35, and 37). 2-[(3,5-Dimorpholino-4H-
1,2,6-thiadiazin-4-ylidene)amino]benzonitrile (33). A solution of 2-
[(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)amino]benzonitrile (29)
(28.3 mg, 0.10 mmol) in neat morpholine (175 μL, 2.00 mmol) was
stirred at ca. 20 °C until no starting material remained (by TLC, 24
h). DCM (10 mL) was then added, and the mixture was adsorbed
onto silica and chromatographed (DCM/t-BuOMe, 90:10) to give
the title compound 33 (37.3 mg, 97%) as red plates, mp (hotstage)
206−207 °C (EtOH); Rf 0.50 (DCM/t-BuOMe, 90:10); (Anal. Calcd
for C18H20N6O2S: C, 56.23; H, 5.24; N, 21.86. Found: C, 56.18; H,
5.39; N, 21.67); λmax(DCM)/nm 248 inf (log ε 4.39), 323 (4.03), 507
(3.62); νmax/cm−1 2978w, 2910w and 2897w (alkyl C-H), 2220m
(CN), 1580s, 1572s, 1526m, 1443m, 1366m, 1304w, 1273m,
1265m, 1250m, 1217w, 1138m, 1113s, 1065m, 1051w, 1007m, 964w,
939w, 876w, 866m, 851m, 835m, 831m, 793m, 762m, 748m, 743m,
737m; 1H NMR (CDCl3, 500 MHz): δ 7.65 (dd, 1H, J = 7.7, 1.3 Hz),
7.45 (ddd, 1H, J = 8.0, 8.0, 1.4 Hz), 7.22 (ddd, 1H, J = 7.7, 7.7, 0.8
Hz), 6.69 (d, 1H, J = 8.1 Hz), 3.88 (t, 4H, J = 4.3 Hz), 3.69 (br s,
4H), 2.87 (br s, 8H); 13C{1H} NMR (CDCl3, 125 MHz): δ 152.0 (s),
147.3 (s), 137.82 (s), 137.78 (s), 132.1 (d), 132.0 (d), 125.1 (d),
119.9 (d), 117.8 (s), 105.4 (s), 66.5 (t), 65.4 (t), 46.4 (t); m/z
(APCI+) 385 (MH+, 100%), 381 (52), 325 (34), 273 (28), 186 (43).
(Z)-2-{[3-Chloro-5-(phenylamino)-4H-1,2,6-thiadiazin-4-
ylidene]amino}benzonitrile (35). To a stirred solution of 2-[(3,5-
dichloro-4H-1,2,6-thiadiazin-4-ylidene)amino]benzonitrile (29) (28.3
mg, 0.100 mmol) in THF (1 mL) at ca. 20 °C was added aniline (18
μL, 0.20 mmol). The mixture was then stirred at this temperature
until no starting material remained (by TLC, 18 h). The reaction
mixture was then adsorbed onto silica and chromatographed (n-
hexane/DCM, 50:50) to give the title compound 35 (33.7 mg, 99%) as
orange needles, mp (hotstage) 146−147 °C (c-hexane); Rf 0.44 (n-
hexane/DCM, 50:50); (Anal. Calcd for C16H10ClN5S: C, 56.56; H,
2.97; N, 20.61. Found: C, 56.68; H, 2.73; N, 20.57); λmax(DCM)/nm
259 inf (log ε 4.18), 282 inf (4.24), 293 inf (4.34), 310 (4.38), 331
(4.34), 344 inf (4.26), 423 (4.20); νmax/cm−1 3242w (N-H), 2226m
(CN), 1591m, 1537s, 1530s, 1497m, 1481w, 1454w, 1439m,
1329m, 1321m, 1281w, 1267w, 1248w, 1219w, 1169m, 1101w,
Reaction of Methyl 2-[(3,5-Dichloro-4H-1,2,6-thiadiazin-4-
ylidene)amino]benzoate (37) with n-Butylamine. To a stirred
solution of methyl 2-[(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)-
amino]benzoate (30) (158 mg, 0.500 mmol) in DCM (4 mL) at ca.
20 °C was added n-butylamine (99 μL, 1.00 mmol). The mixture was
then stirred at this temperature until no starting material remained
(by TLC, 1 h). The reaction mixture was then adsorbed onto silica
and chromatographed (n-hexane/DCM, 50:50) to give the methyl
(Z)-2-{[3-(n-butylamino)-5-chloro-4H-1,2,6-thiadiazin-4-ylidene]-
amino}benzoate (37) (81.5 mg, 46%) as orange plates, mp (hotstage)
63−64 °C (n-hexane/−40 °C); Rf 0.40 (n-hexane/DCM, 50:50);
(Anal. Calcd for C15H17ClN4O2S: C, 51.06; H, 4.86; N, 15.88. Found:
C, 50.88; H, 4.75; N, 15.97); λmax(DCM)/nm 271 (log ε 4.02), 326
(3.85), 455 (4.05); νmax/cm−1 3323w and 3320w (N-H), 2957w,
2926w and 2859w (alkyl C-H), 1705s (CO), 1611m, 1597m,
1560s, 1557s, 1454w, 1435m, 1314m, 1277m, 1250m, 1227w, 1190m,
1157m, 1138w, 1084s, 1067m, 1051w, 966w, 870m, 845m, 826m,
800m, 791m, 760m, 712s; 1H NMR (CDCl3, 300 MHz): δ 7.96 (dd,
1H, J = 8.0, 1.4 Hz), 7.42 (ddd, 1H, J = 7.5, 7.5, 1.5 Hz), 7.19 (br s,
1H), 7.09 (ddd, 1H, J = 7.7, 7.7, 1.2 Hz), 6.69 (dd, 1H, J = 8.0, 0.9
Hz), 3.79 (s, 3H), 3.41 (q, 2H, J = 6.8 Hz), 1.64−1.62 (m, 2H),
1.42−1.40 (m, 2H), 0.95 (t, 3H, J = 7.4 Hz); 13C{1H} NMR (CDCl3,
75 MHz): δ 166.2 (s), 151.4 (s), 151.0 (s), 132.3 (d), 130.8 (s),
130.7 (d), 122.9 (d), 119.8 (d), 118.6 (s), 51.8 (q), 41.1 (t), 31.0 (t),
20.2 (t), 13.8 (q), one C (s) resonance missing; m/z (MALDI-TOF)
355 (MH+ + 2, 69%), 353 (MH+, 100), 323 (41), 321 (82).
Preparation of Aryl[1,2,6]thiadiazino[3,4-b][1,4]diazepin-
10(11H)-ones (4). 4-Chlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]-
diazepin-10(11H)-one (4a) (Typical Procedure A). To a stirred
solution of 2-[(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)amino]-
benzamide (13a) (30.1 mg, 0.100 mmol) in THF (5 mL) at ca. 20
°C was added NaH (4.0 mg, 0.10 mmol, 60% dispersion in mineral
oil). The mixture was then stirred at this temperature until no starting
material remained (by TLC, 15 min). Glacial AcOH (10 μL) and
DCM (10 mL) were then added, and the mixture was adsorbed onto
silica and chromatographed (n-hexane/DCM, 20:80) to give the title
compound 4a (18.1 mg, 68%) as orange needles, mp (hotstage) 214−
215 °C (c-hexane); mp (DSC) onset 218.7 °C, peak max 219.6 °C,
decomp. onset 251.7 °C, peak max 263.8 °C; Rf 0.44 (n-hexane/
DCM, 20:80); (Anal. Calcd for C10H5ClN4OS: C, 45.38; H, 1.90; N,
21.17. Found: C, 45.16; H, 1.82; N, 20.98); λmax(DCM)/nm 247 (log
ε 4.49), 282 (4.29), 292 (4.29), 323 (4.19), 355 (4.19), 433 (4.05);
νmax/cm−1 3213w and 3159w (N-H), 3080w and 3048w (aryl C-H),
1659s (CO), 1599m, 1570m, 1530m, 1506m, 1445m, 1431m,
1375s, 1341s, 1300w, 1211w, 1188m, 1155w, 1130m, 1092w, 972w,
1
1030w, 1001w, 891s, 837w, 787m, 766m, 748m; H NMR (CDCl3,
500 MHz): δ 9.24 (br s, 1H), 7.66−7.63 (m, 3H), 7.53 (ddd, 1H, J =
7.8, 7.8, 1.4 Hz), 7.39 (dd, 1H, J = 7.5, 7.5 Hz), 7.20−7.16 (m, 2H),
6.91 (d, 1H, J = 8.1 Hz); 13C{1H} NMR (CDCl3, 125 MHz): δ 152.1
(s), 148.1 (s), 137.3 (s), 134.0 (s), 132.6 (d), 132.3 (s), 132.2 (d),
129.1 (d), 124.8 (d), 124.0 (d), 120.4 (d), 120.1 (d), 117.2 (s), 103.6
(s); m/z (ES-API+) 342 (MH+ + 2, 16%), 340 (MH+, 38), 325 (M+ −
N, 100).
Methyl 2-[(3,5-Dichloro-4H-1,2,6-thiadiazin-4-ylidene)amino]-
benzoate (30). To a stirred solution of 3,4,4,5-tetrachloro-4H-1,2,6-
thiadiazine (3) (238 mg, 1.00 mmol) in MeCN (4 mL) at ca. 20 °C
was added methyl 2-aminobenzoate (454 mg, 3.00 mmol). The
mixture was then stirred at this temperature until no starting material
remained (by TLC, 1 h). t-BuOMe (10 mL) was then added, and the
precipitate was filtered and washed with n-hexane (5 mL). The filtrate
was then adsorbed onto silica and chromatographed (n-hexane/DCM,
20:80) to give the title compound 30 (297.5 mg, 94%) as orange
plates, mp (hotstage) 77−78 °C (n-hexane/-60 °C); Rf 0.59 (n-
hexane/DCM, 20:80); (Anal. Calcd for C11H7Cl2N3O2S: C, 41.79; H,
2.23; N, 13.29. Found: C, 41.87; H, 2.17; N, 13.38); λmax(DCM)/nm
329 (log ε 4.30), 424 (3.10); νmax/cm−1 3071w (aryl C-H), 2951w
(alkyl C-H), 1709s (CO), 1620m, 1595m, 1476m, 1435m, 1300m,
1273m, 1256s, 1233m, 1206m, 1190m, 1165m, 1138m, 1084s,
1049m, 957m, 883m, 872m, 827m, 802s, 773s, 745s, 719m; 1H NMR
(CDCl3, 500 MHz): δ 7.98 (dd, 1H, J = 7.9, 1.3 Hz), 7.47 (ddd, 1H, J
1
937m, 899m, 872s, 826m, 777s, 745s, 735m; H NMR (CDCl3, 500
MHz): δ 8.16 (dd, 1H, J = 7.9, 1.6 Hz), 7.74 (br s, 1H), 7.59 (ddd,
1H, J = 7.8, 7.8, 1.6 Hz), 7.48 (dd, 1H, J = 8.0, 1.2 Hz), 7.33 (ddd,
1H, J = 7.8, 7.8, 1.3 Hz); 13C{1H} NMR (CDCl3, 125 MHz): δ 163.8
(s), 149.6 (s), 143.8 (s), 143.7 (s), 135.6 (d), 134.52 (d), 134.49 (s),
133.3 (d), 129.4 (d), 122.5 (s); m/z (MALDI-TOF) 267 (MH+ + 2,
32%), 266 (M+ + 2, 37), 265 (MH+, 100), 248 (45), 237 (37).
Further elution (DCM) gave 3′,5′-dichloro-1H-spiro[quinazoline-
2,4′-[1,2,6]thiadiazin]-4(3H)-one (12a) (0.6 mg, 2%) as colorless
needles mp (hotstage) 116−117 °C (c-hexane/THF) (lit.,18 mp 116−
117 °C (c-hexane/THF); Rf 0.13 (DCM); 1H NMR (DMSO-d6, 500
MHz) 8.99 (s, 1H), 8.26 (s, 1H), 7.61 (dd, 2H, J = 7.8, 1.1 Hz), 7.33
(ddd, 1H, J = 7.6, 7.6, 1.5 Hz), 6.73 (dd, 1H, J = 7.6, 7.6 Hz), 6.62 (d,
1H, J = 8.0 Hz), identical to an authentic sample.18
4-Chlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]diazepin-10(11H)-
one (4a) (Typical Procedure B). To a stirred solution of 2-[(3,5-
dichloro-4H-1,2,6-thiadiazin-4-ylidene)amino]benzamide (13a) (30.1
mg, 0.100 mmol) in THF (2 mL) at ca. 20 °C were added
tris{tris[3,5-bis(trifluoromethyl)phenyl]phosphine}palladium [aka
5707
https://doi.org/10.1021/acs.joc.1c00206
J. Org. Chem. 2021, 86, 5702−5713

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Superstable Pd(0)] (2.6 mg, 1.25 mol %), DPEPhos (2.7 mg, 0.0050
mmol), and K2CO3 (20.7 mg, 0.150 mmol). The mixture was then
stirred at this temperature until no starting material remained (by
TLC, 24 h). DCM (10 mL) was then added, and the mixture was
adsorbed onto silica and chromatographed (n-hexane/DCM, 20:80)
to give the title compound 4a (20.2 mg, 76%) as orange needles, mp
(hotstage) 214−215 °C (c-hexane); 1H NMR (CDCl3, 500 MHz): δ
8.16 (dd, 1H, J = 7.9, 1.6 Hz), 7.74 (br s, 1H), 7.59 (ddd, 1H, J = 7.8,
7.8, 1.6 Hz), 7.48 (dd, 1H, J = 8.0, 1.2 Hz), 7.33 (ddd, 1H, J = 7.8,
7.8, 1.3 Hz), identical to that reported above. Further elution (DCM)
gave 3′,5′-dichloro-1H-spiro[quinazoline-2,4′-[1,2,6]-thiadiazin]-
4(3H)-one (12a) (4.0 mg, 13%) as colorless needles mp (hotstage)
116−117 °C (c-hexane/THF) (lit.,18 mp 116−117 °C (c-hexane/
J = 1.8 Hz), 7.45 (dd, 1H, J = 8.1, 1.9 Hz), 7.23 (d, 1H, J = 8.0 Hz),
2.34 (s, 3H); 13C{1H} NMR (DMSO-d6, 125 MHz): δ 164.3 (s),
147.6 (s), 144.8 (s), 141.3 (s), 138.9 (s), 135.9 (s), 135.5 (d), 133.2
(d), 132.6 (d), 123.7 (s), 20.5 (q, CH3); m/z (APCI+) 281 (MH+ + 2,
35%), 279 (MH+, 100), 104 (10). Further elution (DCM/t-BuOMe,
90:10) gave 3′,5′-dichloro-6-methyl-1H-spiro[quinazoline-2,4′-
[1,2,6]thiadiazin]-4(3H)-one (12c) (9.5 mg, 30%) as colorless
needles, mp (hotstage) 217−218 °C (c-hexane/THF) (lit.,18 mp
217−218 °C (c-hexane/THF); Rf 0.48 (n-hexane/t-BuOMe, 50:50);
1H NMR (DMSO-d6, 300 MHz): δ 8.92 (d, 1H, J = 1.6 Hz), 8.10 (d,
1H, J = 1.5 Hz), 7.41 (d, 1H, J = 1.6 Hz), 7.14 (ddd, 1H, J = 8.3, 2.2,
0.5 Hz), 6.54 (d, 1H, J = 8.2 Hz), 2.18 (s, 3H), identical to an
authentic sample.18
1
THF); Rf 0.13 (DCM); H NMR (DMSO-d6, 500 MHz): δ 8.99 (s,
4-Chloro-9-methylbenzo[e][1,2,6]thiadiazino[3,4-b][1,4]-
diazepin-10(11H)-one (4d). Similar treatment (procedure B) of 2-
[(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)amino]-6-methylbenza-
mide (13d) (31.5 mg, 0.100 mmol) gave after chromatography (n-
hexane/DCM, 20:80) the title compound 4d (18.7 mg, 67%) as orange
needles, mp (hotstage) 199−200 °C (c-hexane); Rf 0.80 (n-hexane/
DCM, 20:80); (Anal. Calcd for C11H7ClN4OS: C, 47.40; H, 2.53; N,
20.10. Found: C, 47.36; H, 2.39; N, 19.88); λmax(DCM)/nm 247 (log
ε 4.27), 281 inf (4.06), 349 (4.07), 414 (3.96); νmax/cm−1 3225w and
3173w (N-H), 3057w (aryl C-H), 2951w and 2936w (alkyl C-H),
1678s (CO), 1599w, 1547w, 1520w, 1510m, 1447m, 1433m,
1427m, 1393m, 1383m, 1306m, 1281m, 1229m, 1194m, 1126m,
1078w, 1040w, 974m, 937m, 868m, 837m, 814m, 802s, 773m, 739s;
1H NMR (DMSO-d6, 500 MHz): δ 11.08 (s, 1H), 7.47 (dd, 1H, J =
7.8, 7.8 Hz), 7.24 (d, 1H, d, J = 7.5 Hz), 7.12 (d, 1H, J = 7.8 Hz), 2.42
(s, 3H); 13C{1H} NMR (DMSO-d6, 125 MHz): δ 166.6 (s), 144.4
(s), 144.0 (s), 143.7 (s), 141.1 (s), 138.6 (s), 132.3 (d), 131.8 (d),
129.1 (d), 125.6 (s), 22.1 (q); m/z (APCI+) 281 (MH+ + 2, 34%),
279 (MH+, 100), 153 (19), 130 (93). Further elution (n-hexane/t-
BuOMe, 50:50) gave 3′,5′-dichloro-5-methyl-1H-spiro[quinazoline-
2,4′-[1,2,6]thiadiazin]-4(3H)-one (12d) (2.8 mg, 9%) as colorless
needles, mp (hotstage) 228−229 °C (c-hexane) (lit.,18 mp 229−230
°C (c-hexane); Rf 0.70 (n-hexane/t-BuOMe, 50:50); 1H NMR
(DMSO-d6, 300 MHz): δ 8.74 (d, 1H, J = 1.7 Hz), 8.13 (d, 1H, J
= 1.8 Hz), 7.16 (dd, 1H, J = 7.8, 7.8 Hz), 6.51 (d, 1H, J = 7.4 Hz),
6.47 (d, 1H, J = 8.1 Hz), 2.52 (s, 3H), identical to an authentic
sample.18
1H), 8.26 (s, 1H), 7.61 (dd, 2H, J = 7.8, 1.1 Hz), 7.33 (ddd, 1H, J =
7.6, 7.6, 1.5 Hz), 6.73 (dd, 1H, J = 7.6, 7.6 Hz), 6.62 (d, 1H, J = 8.0
Hz), identical to that reported above.
Conversion of Spirocycle 12a to Diazepine 4a. To a stirred
solution of 3′,5′-dichloro-1H-spiro[quinazoline-2,4′-[1,2,6]-
thiadiazin]-4(3H)-one (12a) (30.1 mg, 0.100 mmol) in THF (5
mL) at ca. 20 °C was added NaH (4.0 mg, 0.10 mmol, 60% dispersion
in mineral oil), and the mixture was then stirred at ca. 66 °C using an
oil bath until no starting material remained (by TLC, 1 h). Glacial
AcOH (10 μL) and DCM (10 mL) were then added, and the mixture
was adsorbed onto silica and chromatographed (n-hexane/DCM,
20:80) to give 4-chlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]-diaze-
pin-10(11H)-one (4a) (8.2 mg, 31%) as orange needles, mp
(hotstage) 214−215 °C (c-hexane), Rf 0.44 (n-hexane/DCM,
1
20:80); H NMR (CDCl3, 500 MHz): δ 8.16 (dd, 1H, J = 7.9, 1.6
Hz), 7.74 (br s, 1H), 7.59 (ddd, 1H, J = 7.8, 7.8, 1.6 Hz), 7.48 (dd,
1H, J = 8.0, 1.2 Hz), 7.33 (ddd, 1H, J = 7.8, 7.8, 1.3 Hz); identical to
that reported above.
4-Chloro-7-methylbenzo[e][1,2,6]thiadiazino[3,4-b][1,4]-
diazepin-10(11H)-one (4b). Similar treatment (procedure A) of 2-
[(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)amino]-4-methylbenza-
mide (13b) (31.5 mg, 0.100 mmol) gave after chromatography
(DCM) the title compound 4b (8.9 mg, 32%) as orange needles, mp
(hotstage) 267−268 °C (c-hexane/THF); Rf 0.63 (DCM); (Anal.
Calcd for C11H7ClN4OS: C, 47.40; H, 2.53; N, 20.10. Found: C,
47.16; H, 2.28; N, 20.38); λmax(DCM)/nm 251 (log ε 4.09), 285
(3.94), 296 (3.94), 350 (3.78), 434 (3.62); νmax/cm−1 3219w and
3171w (N-H), 3051w (aryl C-H), 1667s (CO), 1605m, 1566m,
1510m, 1425w, 1383m, 1325m, 1258w, 1236w, 1194w, 937m, 895m,
876m, 841m, 833m, 756m, 739m; 1H NMR (DMSO-d6, 500 MHz): δ
11.00 (s, 1H), 7.89 (d, 1H, J = 7.9 Hz), 7.19 (d, 1H, J = 8.5 Hz), 7.17
(s, 1H), 2.35 (s, 3H); 13C{1H} NMR (DMSO-d6, 125 MHz): δ 164.1
(s), 147.6 (s), 145.5 (s), 144.8 (s), 143.3 (s), 136.5 (s), 133.3 (d),
132.4 (d), 129.5 (d), 121.4 (s), 20.4 (q); m/z (MALDI-TOF) 281
(MH+ + 2, 55%), 279 (MH+, 87), 263 (25), 251 (13), 244 (60), 238
(56), 236 (100), 216 (26). Further elution (n-hexane/t-BuOMe,
50:50) gave 3′,5′-dichloro-7-methyl-1H-spiro-[quinazoline-2,4′-
[1,2,6]thiadiazin]-4(3H)-one (12b) (3.2 mg, 10%) as colorless
needles, mp (hotstage) 231−232 °C (c-hexane/THF) (lit.,18 mp
4,7-Dichlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]diazepin-10-
(11H)-one (4e). Similar treatment (procedure A) of 4-chloro-2-[(3,5-
dichloro-4H-1,2,6-thiadiazin-4-ylidene)amino]benzamide (13e) (33.6
mg, 0.100 mmol) gave after chromatography (n-hexane/DCM,
20:80) the title compound 4e (13.3 mg, 44%) as orange needles, mp
(hotstage) 246−247 °C (c-hexane); Rf 0.62 (n-hexane/DCM, 20:80);
(Anal. Calcd for C10H4Cl2N4OS: C, 40.15; H, 1.35; N, 18.73. Found:
C, 40.10; H, 1.16; N, 18.49); λmax(DCM)/nm 248 (log ε 4.24), 287
(4.09), 297 (4.10), 356 (3.91), 438 (3.78); νmax/cm−1 3227w and
3173w (N-H), 3053w (aryl C-H), 1670s (CO), 1576w, 1562s,
1508m, 1504m, 1468w, 1422w, 1416s, 1317m, 1304m, 1204m,
1
1138m, 1109w, 1078m, 934m, 897m, 874m, 808m, 749s, 712s; H
NMR (DMSO-d6, 500 MHz): δ 11.13 (s, 1H), 7.98 (d, 1H, J = 8.5
Hz), 7.43 (dd, 1H, J = 8.5, 2.2 Hz), 7.32 (d, 1H, J = 2.2 Hz); 13C{1H}
NMR (DMSO-d6, 125 MHz): δ 163.4 (s), 147.7 (s), 144.97 (s),
144.94 (s), 139.0 (s), 137.7 (s), 134.1 (d), 131.7 (d), 128.1 (d), 123.1
(s); m/z (APCI+) 301 (MH+ + 2, 9%), 299 (MH+, 14), 219 (15), 153
(29), 130 (100). Further elution (DCM/t-BuOMe, 95:5) gave
3′,5′,7-trichloro-1H-spiro[quinazoline-2,4′-[1,2,6]thiadiazin]-4(3H)-
one (12e) (14.1 mg, 42%) as colorless needles, mp (hotstage) 255−
256 °C (c-hexane) (lit.,18 mp 255−256 °C (c-hexane); Rf 0.80
(DCM/t-BuOMe, 95:5); 1H NMR (DMSO-d6, 500 MHz): δ 9.14 (s,
1H), 8.52 (s, 1H), 7.62 (d, 1H, J = 8.3 Hz), 6.77 (dd, 1H, J = 8.4, 1.9
Hz), 6.68 (d, 1H, J = 1.9 Hz), identical to an authentic sample.18
4,8-Dichlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]diazepin-10-
(11H)-one (4f). Similar treatment (procedure A) of 5-chloro-2-[(3,5-
dichloro-4H-1,2,6-thiadiazin-4-ylidene)amino]benzamide (13f) (33.6
mg, 0.100 mmol) gave after chromatography (n-hexane/DCM,
50:50) the title compound 4f (18.6 mg, 62%) as orange plates, mp
(hotstage) 238−239 °C (c-hexane); Rf 0.22 (n-hexane/DCM, 50:50);
1
231−232 °C (c-hexane/THF); Rf 0.57 (DCM/t-BuOMe, 90:10); H
NMR (DMSO-d6, 500 MHz): δ 8.89 (d, 1H, J = 1.2 Hz), 8.16 (d, 1H,
J = 1.2 Hz), 7.49 (d, 1H, J = 7.9 Hz), 6.55 (d, 1H, J = 7.9 Hz), 6.41 (s,
1H), 2.23 (s, 3H), identical to an authentic sample.18
4-Chloro-8-methylbenzo[e][1,2,6]thiadiazino[3,4-b][1,4]-
diazepin-10(11H)-one (4c). Similar treatment (procedure A) of 2-
[(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)amino]-5-methylbenza-
mide (13c) (31.5 mg, 0.100 mmol) gave after chromatography (n-
hexane/DCM, 20:80) the title compound 4c (11.4 mg, 41%) as orange
needles, mp (hotstage) 203−204 °C (c-hexane); Rf 0.42 (n-hexane/
DCM, 20:80); (Anal. Calcd for C11H7ClN4OS: C, 47.40; H, 2.53; N,
20.10. Found: C, 47.54; H, 2.26; N, 20.01); λmax(DCM)/nm 254 (log
ε 4.56), 285 (4.43), 294 (4.43), 323 (4.28), 359 (4.35), 436 (4.22);
νmax/cm−1 3237w and 3190w (N-H), 1678m and 1672s (CO),
1604m, 1562w, 1514m, 1476w, 1422m, 1371s, 1323s, 1217m, 1186m,
1136m, 1098w, 951w, 908m, 895s, 839s, 799s, 793s, 779s, 758m,
727m; 1H NMR (DMSO-d6, 500 MHz): δ 10.98 (s, 1H), 7.81 (d, 1H,
5708
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The Journal of Organic Chemistry
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Article
(Anal. Calcd for C10H4Cl2N4OS: C, 40.15; H, 1.35; N, 18.73. Found:
C, 40.10; H, 1.23; N, 18.56); λmax(DCM)/nm 259 (log ε 4.19), 281
(4.05), 291 (4.02), 359 (4.03), 444 (3.88); νmax/cm−1 3196w and
3134w (N-H), 3042w (aryl C-H), 1649m and 1643s (CO),
1595m, 1562m, 1535w, 1503w, 1462m, 1434m, 1433m, 1408w,
1371s, 1362s, 1215w, 1188w, 1142m, 1107w, 947m, 910m, 901m,
8-Bromo-4-chlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]-
diazepin-10(11H)-one (4i). Similar treatment (procedure A) of 5-
bromo-2-[(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)amino]-
benzamide (13i) (38.0 mg, 0.100 mmol) gave after chromatography
(n-hexane/DCM, 50:50) the title compound 4i (23.8 mg, 69%) as
orange needles, mp (hotstage) 193−194 °C (c-hexane); Rf 0.26 (n-
hexane/DCM, 50:50); (Anal. Calcd for C10H4BrClN4OS: C, 34.96;
H, 1.17; N, 16.31. Found: C, 34.92; H, 1.08; N, 16.28); λmax(DCM)/
nm 261 (log ε 4.04), 282 inf (3.92), 291 inf (3.89), 360 (3.93), 446
(3.77); νmax/cm−1 3196w and 3138w (N-H), 3042w (aryl C-H),
1643s (CO), 1591m, 1560w, 1530m, 1503w, 1433m, 1402w,
1371s, 1321s, 1213w, 1188w, 1142m, 1096m, 943m, 901m, 878m,
1
885m, 860m, 843m, 835s, 762m, 702s; H NMR (DMSO-d6, 500
MHz): δ 11.17 (s, 1H), 7.91 (d, 1H, J = 2.6 Hz), 7.68 (dd, 1H, J =
8.5, 2.6 Hz), 7.32 (d, 1H, J = 8.5 Hz); 13C{1H} NMR (DMSO-d6, 125
MHz): δ 163.1 (s), 147.8 (s), 144.8 (s), 142.6 (s), 137.0 (s), 134.9
(d), 134.5 (d), 132.6 (s), 131.4 (d), 125.8 (s); m/z (APCI+) 301
(MH+ + 2, 19%), 299 (MH+, 25), 242 (100), 130 (15). Further
elution (DCM/t-BuOMe, 90:10) gave 3′,5′,6-trichloro-1H-spiro-
[quinazoline-2,4′-[1,2,6]-thiadiazin]-4(3H)-one (12f) (10.4 mg,
31%) as colorless plates, mp (hotstage) 164−165 °C (PhH/c-
hexane) (lit.,18 mp 164−165 °C (PhH/c-hexane); Rf 0.81 (DCM/t-
1
854m, 833s, 752m; H NMR (DMSO-d6, 500 MHz): δ 11.16 (br s,
1H), 8.04 (d, 1H, J = 2.5 Hz), 7.80 (dd, 1H, J = 8.5, 2.5 Hz), 7.23 (d,
1H, J = 8.5 Hz); 13C{1H} NMR (DMSO-d6, 125 MHz): δ 163.0 (s),
147.7 (s), 144.9 (s), 142.9 (s), 137.4 (d), 137.1 (s), 135.0 (d), 134.3
(d), 125.9 (s), 121.0 (s); m/z (APCI+) 347 (MH+ + 4, 18%), 345
(MH+ + 2, 58), 343 (MH+, 46), 242 (100), 130 (58). Further elution
(DCM/t-BuOMe, 90:10) gave 6-bromo-3′,5′-dichloro-1H-spiro-
[quinazoline-2,4′-[1,2,6]thiadiazin]-4(3H)-one (12i) (10.6 mg,
28%) as colorless needles, mp (hotstage) 206−207 °C (CHCl3)
(lit.,18 mp 206−207 °C (CHCl3); Rf 0.76 (DCM/t-BuOMe, 90:10);
1H NMR (DMSO-d6, 300 MHz): δ 9.19 (s, 1H), 8.48 (s, 1H), 7.55
1
BuOMe, 90:10); H NMR (DMSO-d6, 500 MHz): δ 9.19 (s, 1H),
8.48 (s, 1H), 7.55 (d, 1H, J = 2.6 Hz), 7.37 (dd, 1H, J = 8.7, 2.6 Hz),
6.68 (d, 1H, J = 8.7 Hz), identical to an authentic sample.18
4,9-Dichlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]diazepin-10-
(11H)-one (4g). Similar treatment (procedure A) of 2-chloro-6-[(3,5-
dichloro-4H-1,2,6-thiadiazin-4-ylidene)amino]benzamide (13g) (33.6
mg, 0.100 mmol) gave after chromatography (n-hexane/DCM,
50:50) the title compound 4g (19.5 mg, 65%) as orange plates, mp
(hotstage) 195−196 °C (c-hexane); Rf 0.22 (n-hexane/DCM, 50:50);
(Anal. Calcd for C10H4Cl2N4OS: C, 40.15; H, 1.35; N, 18.73. Found:
C, 39.84; H, 1.62; N, 18.67); λmax(DCM)/nm 319 (log ε 4.08), 351
(4.12), 417 inf (3.76); νmax/cm−1 3154w (N-H), 3053w (aryl C-H),
1659s (CO), 1599w, 1572m, 1503w, 1435w, 1377m, 1325m,
1267w, 1233w, 1198w, 1180w, 1126w, 957m, 866m, 808m, 802m,
(s, 1H), 7.37 (d, 1H, J = 8.9 Hz), 6.68 (d, 1H, J = 8.8 Hz), identical to
an authentic sample.18
9-Bromo-4-chlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]-
diazepin-10(11H)-one (4j). Similar treatment (procedure A) of 2-
bromo-6-[(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)amino]-
benzamide (13j) (38.0 mg, 0.100 mmol) gave after chromatography
(n-hexane/DCM, 20:80) the title compound 4j (7.0 mg, 20%) as
orange plates, mp (hotstage) 193−194 °C (n-hexane/DCM); Rf 0.31
(n-hexane/DCM, 20:80); (Anal. Calcd for C10H4BrClN4OS: C,
34.96; H, 1.17; N, 16.31. Found: C, 35.05; H, 1.16; N, 16.48);
λmax(DCM)/nm 252 inf (log ε 4.04), 285 inf (3.82), 335 (3.89), 415
(3.81); νmax/cm−1 3152w (N-H), 3057w (aryl C-H), 1659s (CO),
1599w, 1566m, 1558m, 1547w, 1503m, 1433m, 1377m, 1325m,
1267w, 1231w, 1196w, 1184w, 1121w, 951m, 864m, 804m, 764m,
1
746s; H NMR (DMSO-d6, 300 MHz): δ 11.30 (s, 1H), 7.55 (dd,
1H, J = 8.0, 8.0 Hz), 7.46 (dd, 1H, J = 8.0, 1.4 Hz), 7.21 (dd, 1H, J =
7.9, 1.4 Hz); 13C{1H} NMR (DMSO-d6, 75 MHz): δ 164.0 (s), 145.4
(s), 144.1 (s), 143.6 (s), 140.3 (s), 133.7 (s), 133.2 (d), 130.5 (d),
129.7 (d), 125.8 (s); m/z (APCI+) 303 (MH+ + 4, 16%), 301 (MH+
+ 2, 72), 299 (MH+, 100), 154 (64), 104 (10). Further elution (n-
hexane/t-BuOMe, 50:50) gave 3′,5,5′-trichloro-1H-spiro[quinazoline-
2,4′-[1,2,6]thiadiazin]-4(3H)-one (12g) (11.2 mg, 33%) as colorless
needles, mp (hotstage) 231−232 °C (c-hexane/THF) (lit.,18 mp
231−232 °C (c-hexane/THF); Rf 0.43 (n-hexane/t-BuOMe, 50:50);
1H NMR (DMSO-d6, 300 MHz): δ 9.00 (d, 1H, J = 1.7 Hz), 8.52 (d,
1
741s, 723m; H NMR (DMSO-d6, 500 MHz): δ 11.32 (br s, 1H),
7.64 (d, 1H, J = 7.9 Hz), 7.45 (dd, 1H, J = 8.0, 8.0 Hz), 7.23 (d, 1H, J
= 7.9 Hz); 13C{1H} NMR (DMSO-d6, 125 MHz): δ 164.8 (s), 145.4
(s), 144.0 (s), 143.6 (s), 140.3 (s), 133.9 (d), 133.4 (d), 130.2 (d),
127.6 (s), 122.5 (s); m/z (MALDI-TOF) 345 (MH+ + 2, 100%), 343
(MH+, 100), 310 (9), 308 (11), 302 (50), 300 (47), 264 (11), 113
(12). Further elution (n-hexane/t-BuOMe, 50:50) gave 5-bromo-
3′,5′-dichloro-1H-spiro[quinazoline-2,4′-[1,2,6]thiadiazin]-4(3H)-
one (12j) (9.2 mg, 24%) as colorless needles, mp (hotstage) 229−
230 °C (c-hexane/THF) (lit.,18 mp 229−230 °C (c-hexane/THF); Rf
1H, J = 1.8 Hz), 7.27 (dd, 1H, J = 8.1, 8.1 Hz), 6.75 (dd, 1H, J = 7.9,
1.0 Hz), 6.61 (dd, 1H, J = 8.2, 1.0 Hz), identical to an authentic
sample.18
7-Bromo-4-chlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]-
diazepin-10(11H)-one (4h). Similar treatment (procedure A) of 4-
bromo-2-[(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)amino]-
benzamide (13h) (38.0 mg, 0.100 mmol) gave after chromatography
(n-hexane/DCM, 20:80) the title compound 4h (20.5 mg, 60%) as
orange needles, mp (hotstage) 263−264 °C (c-hexane/THF); Rf 0.31
(n-hexane/DCM, 20:80); (Anal. Calcd for C10H4BrClN4OS: C,
34.96; H, 1.17; N, 16.31. Found: C, 34.85; H, 1.09; N, 16.24);
λmax(DCM)/nm 238 (log ε 4.50), 284 (4.36), 295 (4.37), 362 (4.16),
463 (4.02); νmax/cm−1 3217w and 3167w (N-H), 3080w and 3051w
(aryl C-H), 1670s (CO), 1587w, 1557m, 1504m, 1422m, 1379s,
1315m, 1302w, 1206m, 1138m, 1072w, 943w, 872m, 814m, 746s; 1H
NMR (DMSO-d6, 300 MHz): δ 11.10 (br s, 1H), 7.89 (d, 1H, J = 8.5
Hz), 7.56 (dd, 1H, J = 8.5, 2.1 Hz), 7.46 (d, 1H, J = 2.0 Hz); 13C{1H}
NMR (DMSO-d6, 75 MHz): δ 163.6 (s), 147.8 (s), 144.99 (s),
144.95 (s), 137.7 (s), 134.7 (d), 134.1 (d), 131.1 (d), 127.9 (s), 123.5
(s); m/z (MALDI-TOF) 345 (MH+ + 2, 91%), 343 (MH+, 100), 302
(42), 300 (41), 264 (10), 113 (10). Further elution (DCM/t-
BuOMe, 90:10) gave 7-bromo-3′,5′-dichloro-1H-spiro[quina-zoline-
2,4′-[1,2,6]thiadiazin]-4(3H)-one (12h) (13.8 mg, 36%) as colorless
plates, mp (hotstage) 245−246 °C (n-hexane/t-BuOMe) (lit.,18 mp
245−246 °C (n-hexane/t-BuOMe); Rf 0.57 (DCM/t-BuOMe,
1
0.70 (n-hexane/t-BuOMe, 50:50); H NMR (DMSO-d6, 300 MHz):
δ 9.02 (d, 1H, J = 1.5 Hz), 8.52 (d, 1H, J = 1.7 Hz), 7.17 (dd, 1H, J =
8.0, 8.0 Hz), 6.97 (d, 1H, J = 7.8 Hz), 6.65 (d, 1H, J = 8.3 Hz),
identical to an authentic sample.18
Reactions of 4-Chlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]-
diazepin-10(11H)-one (4a). 4-(Pyrrolidin-1-yl)benzo[e][1,2,6]-
thiadiazino[3,4-b][1,4]diazepin-10(11H)-one (15). To a stirred
solution of 4-chlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]diazepin-
10(11H)-one (4a) (26.5 mg, 0.100 mmol) in THF (0.5 mL) at ca.
20 °C was added pyrrolidine (17 μL, 0.20 mmol), and the mixture
was stirred at this temperature until no starting material remained
(TLC, 1 h). The reaction mixture was then adsorbed onto silica and
chromatographed (DCM) to give the title compound 15 (26.8 mg,
89%) as dark red needles, mp (hotstage) 157−158 °C (c-hexane); Rf
0.40 (DCM); (Anal. Calcd for C14H13N5OS: C, 56.17; H, 4.38; N,
23.40. Found: C, 56.04; H, 4.26; N, 23.26); λmax(DCM)/nm 255 inf
(log ε 4.40), 288 inf (4.12), 321 (4.02), 375 (3.95), 482 (4.00); νmax
/
cm−1 3179w (N-H), 3115w and 3015w (aryl C-H), 2976w, 2916w
and 2872w (alkyl C-H), 1643s (CO), 1593w, 1551m, 1483m,
1468m, 1441m, 1412s, 1364m, 1337m, 1317m, 1292w, 1246m,
1224w, 1202w, 1148m, 1103w, 1090m, 1034w, 964w, 926m, 903m,
881m, 866m, 856m, 822m, 775m, 764m, 754s; 1H NMR (CDCl3, 500
MHz): δ 8.10 (dd, 1H, J = 7.9, 1.6 Hz), 7.70 (br s, 1H), 7.51 (ddd,
1
90:10); H NMR (DMSO-d6, 300 MHz): δ 9.15 (d, 1H, J = 1.3
Hz), 8.52 (d, 1H, J = 1.3 Hz), 7.54 (d, 1H, J = 8.2 Hz), 6.91 (dd, 1H,
J = 8.3, 1.8 Hz), 6.82 (d, 1H, J = 1.8 Hz), identical to an authentic
sample.18
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Article
1H, J = 7.7, 7.7, 1.7 Hz), 7.28 (dd, 1H, J = 7.9, 1.1 Hz), 7.24 (dd, 1H,
J = 7.6, 1.3 Hz), 3.72 (br s, 4H), 1.96−1.93 (m, 4H); 13C{1H} NMR
(CDCl3, 125 MHz): δ 166.2 (s), 150.0 (s), 145.5 (s), 137.9 (s), 137.8
(s), 134.4 (d), 132.9 (d), 131.8 (d), 127.4 (d), 123.7 (s), 49.7 (t),
one C (t) resonance missing; m/z (MALDI-TOF) 299 (M+, 88%),
298 (M+ − H, 95), 281 (16), 269 (75), 257 (58), 252 (29), 230 (63),
203 (15), 69 (100).
(48.3 mg). The filtrate was then extracted with t-BuOMe (2 × 10
mL), dried over Na2SO4, and evaporated to give a further 9.3 mg
(total of 57.6 mg, 93%) of 4k as orange plates, mp (hotstage) 217−
218 °C (c-hexane/THF); Rf 0.50 (DCM); (Anal. Calcd for
C10H4ClN5O3S: C, 38.78; H, 1.30; N, 22.61. Found: C, 38.96; H,
1.44; N, 22.38); λmax(DCM)/nm 247 inf (log ε 4.37), 296 (4.26), 313
inf (4.17), 367 (4.17), 468 (4.20); νmax/cm−1 3235w, 3150w and
3123w (N-H), 1661s, 1612m, 1580m, 1563m, 1518m (NO2), 1495m,
1460w, 1429m, 1379m, 1337s (NO2), 1244w, 1217w, 1142m, 1126m,
4-(Phenylthio)benzo[e][1,2,6]thiadiazino[3,4-b][1,4]diazepin-10-
(11H)-one (16). To a stirred solution of 4-chlorobenzo[e][1,2,6]-
thiadiazino[3,4-b][1,4]diazepin-10(11H)-one (4a) (26.5 mg, 0.100
mmol) in THF (1 mL) at ca. 0 °C, under an argon atmosphere, was
added thiophenol (21 μL, 0.20 mmol), followed by a dropwise
addition of Et3N (28 μL, 0.20 mmol), and the mixture was stirred at
this temperature for 30 min and then warmed to ca. 20 °C and stirred
until no starting material remained (TLC, 6 h). The reaction mixture
was then adsorbed onto silica and chromatographed (n-hexane/DCM,
20:80) to give the title compound 16 (27.7 mg, 82%) as red needles,
mp (hotstage) 247−248 °C (c-hexane/DCE); Rf 0.38 (n-hexane/
DCM, 20:80); (Anal. Calcd for C16H10N4OS2: C, 56.79; H, 2.98; N,
16.56. Found: C, 56.95; H, 2.73; N, 16.36); λmax(DCM)/nm 261 (log
ε 4.16), 344 (3.82), 367 inf (3.81), 456 (3.72); νmax/cm−1 3196w (N-
H), 3115w and 3030w (aryl C-H), 1659m and 1645s (CO),
1597m, 1566m, 1557m, 1483m, 1466m, 1441m, 1423m, 1381m,
1348m, 1215w, 1177w, 1134m, 1022w, 937w, 887w, 874m, 830w,
1
1074m, 961w, 930w, 897m, 816s, 746m; H NMR (DMSO-d6, 300
MHz): δ 11.38 (br s, 1H), 8.65 (d, 1H, J = 2.8 Hz), 8.36 (dd, 1H, J =
8.8, 2.8 Hz), 7.49 (d, 1H, J = 8.8 Hz); 13C{1H} NMR (DMSO-d6, 75
MHz): δ 162.7 (s), 149.0 (s), 148.4 (s), 145.6 (s), 145.4 (s), 138.9
(s), 134.4 (d), 129.1 (d), 127.4 (d), 125.2 (s); m/z (MALDI-TOF)
312 (MH+ + 2, 56%), 310 (MH+, 100), 265 (MH+ − NO2, 66), 264
(M+ − NO2, 36), 263 (M+ − NS, 13).
4-Chloro-11-methylbenzo[e][1,2,6]thiadiazino[3,4-b][1,4]-
diazepin-10(11H)-one (18). To a stirred solution of 4-chlorobenzo-
[e][1,2,6]thiadiazino[3,4-b][1,4]diazepin-10(11H)-one (4a) (26.5
mg, 0.100 mmol) in THF (2 mL) cooled to ca. 0 °C via a water/
ice bath was added NaH (8.0 mg, 0.20 mmol, 60% dispersion in
mineral oil), and the mixture was stirred for 5 min. CH3I (25 μL, 0.40
mmol) was then added, and the mixture warmed to ca. 20 °C over 30
min and stirred for an additional 1.5 h. The mixture was then
adsorbed onto silica and chromatographed (n-hexane/DCM, 30:70)
to give the title compound 18 (25.6 mg, 92%) as yellow needles, mp
(hotstage) 97−98 °C (n-pentane/t-BuOMe/-40 °C); Rf 0.67 (n-
hexane/DCM, 30:70); (Anal. Calcd for C11H7ClN4OS: C, 47.40; H,
2.53; N, 20.10. Found: C, 47.51; H, 2.47; N, 19.95); λmax(DCM)/nm
1
779w, 770w, 760m, 746s, 739m; H NMR (DMSO-d6, 500 MHz): δ
10.86 (s, 1H), 8.02 (dd, 1H, J = 8.4, 1.8 Hz), 7.63 (ddd, 1H, J = 7.6,
7.6, 1.6 Hz), 7.54−7.51 (m, 2H), 7.47−7.46 (m, 3H), 7.36−7.33 (m,
2H); 13C{1H} NMR (DMSO-d6, 125 MHz): δ 163.8 (s), 162.3 (s),
144.0 (s), 142.0 (s), 135.7 (s), 135.4 (d), 135.0 (d), 132.8 (d), 132.6
(d), 129.6 (s), 129.4 (d), 129.3 (d), 128.4 (d), 124.2 (s); m/z
(MALDI-TOF) 338 (M+, 100%), 261 (36), 229 (16), 194 (11), 142
(29).
248 (log ε 4.54), 278 inf (4.25), 352 (4.24), 400 inf (4.09); νmax
/
cm−1 3065w (aryl C-H), 2957w, 2926w and 2868w (alkyl C-H),
1721m, 1665m, 1659m, 1605m, 1580m, 1493m, 1454m, 1414w,
1346m, 1323s, 1263m, 1217m, 1180w, 1107m, 1086m, 1054m,
4-Phenylbenzo[e][1,2,6]thiadiazino[3,4-b][1,4]diazepin-10(11H)-
one (17). To a stirred solution of 4-chlorobenzo[e][1,2,6]thiadiazino-
[3,4-b][1,4]diazepin-10(11H)-one (4a) (52.9 mg, 0.200 mmol) in
PhMe (1 mL) at ca. 20 °C were added tributylphenylstannane (80.8
mg, 0.220 mmol) and Pd(Ph3P)2Cl2 (7.0 mg, 5 mol %). The solution
was then deaerated by bubbling into the reaction mixture Ar gas for
10 min. The reaction mixture was then heated at ca. 110 °C using an
oil bath, under Ar, until no starting material remained (TLC, 2 h).
The reaction mixture was then cooled to ca. 20 °C, t-BuOMe (10
mL) added, and the organic phase was washed with saturated aqueous
KF (10 mL), then dried (Na2SO4), adsorbed onto silica, and
chromatographed (n-hexane/DCM, 80:20) to give the title compound
17 (39.0 mg, 64%) as orange needles, mp (hotstage) 172−173 °C (c-
hexane); Rf 0.45 (n-hexane/DCM, 20:80); (Anal. Calcd for
C16H10N4OS: C, 62.73; H, 3.29; N, 18.29. Found: C, 62.68; H,
3.32; N, 18.14); λmax(DCM)/nm 256 inf (log ε 4.53), 289 inf (4.32),
372 (4.24); νmax/cm−1 3215w (N-H), 3130w and 3042w (aryl C-H),
1672s and 1667s (CO), 1597w, 1572m, 1558m, 1535m, 1439m,
1377m, 1350s, 1292m, 1250m, 1188w, 1148m, 1121w, 1096w, 959w,
872m, 831m, 785m, 779m, 766m, 748m, 733s, 712m; 1H NMR
(DMSO-d6, 500 MHz): δ 11.17 (s, 1H), 7.96 (dd, 1H, J = 7.9, 1.6
Hz), 7.94 (dd, 2H, J = 7.8, 1.4 Hz), 7.58 (ddd, 1H, J = 7.7, 7.7, 1.6
Hz), 7.47−7.40 (m, 3H), 7.36 (ddd, 1H, J = 7.9, 7.9, 1.1 Hz), 7.09
(dd, 1H, J = 7.8, 0.8 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 165.8
(s), 157.5 (s), 144.9 (s), 143.0 (s), 139.2 (s), 135.5 (s), 134.9 (d),
133.0 (d), 132.9 (d), 130.2 (d), 128.7 (d), 128.2 (d), 127.9 (d), 123.1
(s); m/z (APCI+) 307 (MH+, 100%), 153 (15), 130 (46).
Nitration of 4-Chlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]-
diazepin-10(11H)-one (4a). To a stirred sample of 4-chlorobenzo-
[e][1,2,6]thiadiazino[3,4-b][1,4]diazepin-10(11H)-one (4a) (53.0
mg, 0.200 mmol) was added concentrated H2SO4 (1 mL), and the
mixture was cooled to ca. 0 °C with a water-ice bath. Then, KNO3
(20.2 mg, 0.200 mmol) was added in one portion and the mixture
stirred at this temperature until complete consumption of the starting
material (TLC, 5 min). The mixture was then poured onto crushed
ice, and the orange precipitate that formed was filtered, washed with
H2O (2 × 10 mL), and dried under vacuum to give 4-chloro-8-
nitrobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]diazepin-10(11H)-one (4k)
1
1020w, 991m, 893m, 845m, 777m, 754s, 723m; H NMR (CDCl3,
500 MHz): δ 8.06 (dd, 1H, J = 7.9, 1.4 Hz), 7.58 (ddd, 1H, J = 7.8,
7.8, 1.6 Hz), 7.41 (d, 1H, J = 7.9 Hz), 7.36 (dd, 1H, J = 7.7, 7.7 Hz),
3.43 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz): δ 166.9 (s), 144.3
(s), 144.2 (s), 143.6 (s), 139.6 (s), 134.0 (d), 133.3 (d), 131.6 (d),
128.9 (d), 126.4 (s), 36.4 (q, CH3N); m/z (APCI+) 281 (MH+ + 2,
30%), 279 (MH+, 100), 236 (25).
2-Amino-N-(5-chloro-4-oxo-4H-1,2,6-thiadiazin-3-yl)benzamide
(19). To a stirred solution of 4-chlorobenzo[e][1,2,6]thiadiazino[3,4-
b][1,4]diazepin-10(11H)-one (4a) (26.5 mg, 0.100 mmol) in THF
(1 mL) at ca. 20 °C was added 6 M aqueous HCl (1 mL), and the
solution was stirred at this temperature until no starting material
remained (TLC, 30 min). DCM (10 mL) and saturated aqueous
Na2CO3 (10 mL) were added and the phases separated. The aqueous
phase was extracted with DCM (2 × 10 mL), and the combined
organic phase was dried (Na2SO4), adsorbed onto silica, and
chromatographed (DCM) to give the title compound 19 (26.9 mg,
95%) as yellow plates, mp (hotstage) 170−171 °C (c-hexane); Rf 0.81
(DCM); (Anal. Calcd for C10H7ClN4O2S: C, 42.49; H, 2.50; N,
19.82. Found: C, 42.55; H, 2.46; N, 19.91); λmax(DCM)/nm 303 (log
ε 3.86), 314 inf (3.84), 358 (3.99); νmax/cm−1 3466w, 3449w, 3364w
and 3333w (N-H), 1682m, 1640m, 1632m, 1612m, 1585m, 1557m,
1493s, 1477s, 1323w, 1223s, 1198m, 1165m, 1059m, 1047m, 999w,
897m, 853w, 799w, 783m, 746m, 729m; 1H NMR (CDCl3, 500
MHz): δ 9.98 (s, 1H), 7.52 (dd, 1H, J = 8.3, 1.3 Hz), 7.33 (ddd, 1H, J
= 7.2, 7.2, 1.4 Hz), 7.75−6.72 (m, 2H), 5.90 (br s, 2H); 13C{1H}
NMR (CDCl3, 125 MHz): δ 165.7 (s), 156.3 (s), 150.9 (s), 148.2 (s),
146.1 (s), 134.8 (d), 127.6 (d), 118.0 (d), 116.9 (d), 112.3 (s); m/z
(MALDI-TOF) 284 (M+ + 2, 33%), 282 (M+, 100), 120 (16).
Cyclodehydration of Carboxamide 19 to Diazepine 4a. To a
stirred solution of 2-amino-N-(5-chloro-4-oxo-4H-1,2,6-thiadiazin-3-
yl)benzamide (19) (28.3 mg, 0.100 mmol) in PhH (20 mL) at ca. 20
°C was added TsOH·H2O (19 mg, 0.10 mmol), and the mixture was
then stirred at ca. 80 °C using an oil bath under a Dean−Stark
condenser until no starting material remained (by TLC, 18 h). The
mixture was adsorbed onto silica and chromatographed (n-hexane/
DCM, 20:80) to give 4-chlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]-
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diazepin-10(11H)-one (4a) (18.3 mg, 69%) as orange needles, mp
(hotstage) 214−215 °C (c-hexane), Rf 0.44 (n-hexane/DCM, 20:80);
1H NMR (CDCl3, 500 MHz): δ 8.16 (dd, 1H, J = 7.9, 1.6 Hz), 7.74
(br s, 1H), 7.59 (ddd, 1H, J = 7.8, 7.8, 1.6 Hz), 7.48 (dd, 1H, J = 8.0,
1.2 Hz), 7.33 (ddd, 1H, J = 7.8, 7.8, 1.3 Hz); identical to that reported
above.
[e][1,2,6]thiadiazino[3,4-b][1,4]diazepin-10(11H)-one (27.9 mg,
0.100 mmol) gave after 3 d the title compound 20b (25.9 mg, 93%)
as colorless needles, mp (hotstage) 216−217 °C (MeOH); Rf 0.19
(DCM); (Anal. Calcd for C11H7ClN4OS: C, 47.40; H, 2.53; N, 20.10.
Found: C, 47.23; H, 2.39; N, 19.98); λmax(DCM)/nm 258 (log ε
3.97), 303 inf (3.97), 316 (4.11), 328 (4.10), 339 (4.10), 355 inf
(3.85); νmax/cm−1 3267w and 3237w (N-H), 2928w (C-H), 1676s,
1624m, 1605m, 1487m, 1441m, 1371w, 1337w, 1288w, 1250w,
1179w, 1140w, 1101w, 1094w, 1051w, 934m, 909m, 831m, 799m,
782m, 773m; 1H NMR (CDCl3, 300 MHz): δ 10.00 (br s, 1H), 8.15
(s, 1H), 7.82 (d, 1H, J = 8.3 Hz), 7.66 (d, 1H, J = 7.9 Hz), 2.54 (s,
3H); 13C{1H} NMR (DMSO-d6, 75 MHz): δ 161.1 (s), 150.4 (s),
145.6 (s), 144.3 (s), 144.2 (s), 138.3 (s), 136.3 (d), 127.8 (d), 125.5
(d), 121.7 (s), 21.0 (q); m/z (MALDI-TOF) 281 (MH+ + 2, 60%),
279 (MH+, 100).
6-Chloro-2-(4-chloro-1,2,5-thiadiazol-3-yl)quinazolin-4(3H)-one
(20c). Similar treatment (procedure C) of 4,8-dichlorobenzo[e]-
[1,2,6]thiadiazino[3,4-b][1,4]diazepin-10(11H)-one (29.9 mg, 0.100
mmol) with MeOH (4.5 mL) and glacial AcOH (0.50 mL) gave after
6 d the title compound 20c (20.4 mg, 68%) as colorless needles, mp
(hotstage) 240−241 °C (MeOH); Rf 0.35 (DCM); (Anal. Calcd for
C10H4Cl2N4OS: C, 40.15; H, 1.35; N, 18.73. Found: C, 39.76; H,
1.68; N, 18.62); λmax(DCM)/nm 254 (log ε 4.19), 302 inf (4.30), 315
(4.44), 325 inf (4.41), 338 (4.39), 354 inf (4.11); νmax/cm−1 3267w
(N-H), 2951w, 2924w and 2853w (C-H), 1686s, 1611m, 1601m,
1485m, 1470m, 1433m, 1416m, 1371w, 1327m, 1306w, 1277m,
1244w, 1225w, 1173w, 1136m, 1111w, 1094w, 1069w, 1047w, 932m,
887m, 839m, 793m, 766m, 746m; 1H NMR (DMSO-d6, 500 MHz): δ
13.02 (br s, 1H), 8.14 (d, 1H, J = 2.4 Hz), 7.93 (dd, 1H, J = 8.7, 2.5
Hz), 7.82 (d, 1H, J = 8.7 Hz); 13C{1H} NMR (DMSO-d6, 125 MHz):
δ 160.3 (s), 150.1 (s), 146.4 (s), 145.5 (s), 144.4 (s), 135.1 (d), 132.5
(s), 130.1 (d), 125.2 (d), 123.3 (s); m/z (MALDI-TOF) 301 (MH+
+ 2, 63%), 299 (MH+, 100).
Reaction of 4-Chlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]-
diazepin-10(11H)-one (4a) with AcOH. A stirred solution of 4-
chlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]-diazepin-10(11H)-one
(4a) (26.5 mg, 0.100 mmol) in glacial AcOH (1 mL) was heated to
ca. 117 °C using an oil bath, until no starting material remained
(TLC, 3 h). The reaction mixture was left to cool to ca. 20 °C, and n-
hexane (5 mL) was added, which led to the precipitation of a pink
solid. The solid was filtered, washed with n-hexane (5 mL), and dried
under vacuum to give 4-hydroxybenzo[e][1,2,6]thiadiazino[3,4-b]-
[1,4]diazepin-10(11H)-one (21) (7.4 mg, 30%) as red needles, mp
(hotstage) 263 °C (decomp., AcOH/Et2O); mp (DSC) decomp.
onset 290.4 °C, peak max 294.7 °C; Rf 0.26 (DCM/t-BuOMe,
90:10); (Anal. Calcd for C10H6N4O2S: C, 48.78; H, 2.46; N, 22.75.
Found: C, 48.99; H, 2.31; N, 22.66); λmax(DCM)/nm 274 (log ε
4.11), 390 (3.72), 492 inf (4.02), 524 (4.18), 558 (4.12); νmax/cm−1
3150w and 3113w (N-H), 3053w and 3042w (aryl C-H), 1657m and
1651m (CO), 1607m, 1593m, 1574m, 1549m, 1491s, 1441w,
1408w, 1358m, 1335m, 1314w, 1292w, 1263m, 1182w, 1169m,
1117w, 1098w, 1063w, 968m, 955w, 872w, 833m, 802w, 777m, 745s;
1H NMR (CF3CO2D, 500 MHz): δ 8.23 (d, 1H, J = 7.9 Hz), 7.67
(dd, 1H, J = 7.5, 7.5 Hz), 7.42 (dd, 1H, J = 7.7, 7.7 Hz), 7.31 (d, 1H, J
= 7.9 Hz), NH and OH deuterium exchanged; 13C{1H} NMR
(DMSO-d6, 125 MHz): δ 163.5 (s), 159.7 (s), 140.2 (s), 139.7 (s),
134.9 (d), 133.3 (d), 131.7 (s), 124.8 (d), 122.9 (d), 120.5 (s); m/z
(MALDI-TOF) 247 (MH+, 100%), 204 (8). Attempted sublimation
of hydroxydiazepine 21 under a static vacuum (15 mbar, 250 °C)
gave 4-oxo-3,4-dihydroquinazoline-2-carboxamide (22) as colorless
plates, mp (hotstage) 228−229 °C (lit.,28 mp 231−233 °C), 1H NMR
(DMSO-d6, 500 MHz): δ 12.02 (br s, 1H), 8.37 (br s, 1H), 8.17 (d,
1H, J = 7.3 Hz), 8.08 (br s, 1H), 7.88 (dd, 1H, J = 6.7, 6.7 Hz), 7.77
(d, 1H, J = 7.9 Hz), 7.61 (dd, 1H, J = 7.9, 7.9 Hz), identical to the
one reported.28 The filtrate was then adsorbed onto silica and
chromatographed (DCM) to give 2-(4-chloro-1,2,5-thiadiazol-3-
yl)quinazolin-4(3H)-one (20a) (11.4 mg, 43%) as colorless needles,
mp (hotstage) 253−254 °C (DCE); Rf 0.35 (DCM); (found: C,
45.23; H, 1.84; N, 20.98. C10H5ClN4OS requires C, 45.38; H, 1.90;
N, 21.17%); λmax(DCM)/nm 254 (log ε 4.14), 298 inf (4.17), 308
(4.29), 321 (4.28), 332 (4.25), 346 inf (4.00); νmax/cm−1 3231w (N-
H), 1682s (CO), 1601m, 1493w, 1468w, 1441w, 1377w, 1331w,
1315w, 1244w, 1175w, 1134m, 1049w, 1022w, 932m, 881w, 829w,
804m, 775s; 1H NMR (DMSO-d6, 500 MHz): δ 12.8 (br s, 1H), 8.21
(dd, 1H, J = 8.0, 1.3 Hz), 7.91 (ddd, 1H, J = 7.3, 7.3, 1.5 Hz), 7.80 (d,
1H, J = 8.0 Hz), 7.65 (ddd, 1H, J = 7.5, 7.5, 1.0 Hz); 13C{1H} NMR
(DMSO-d6, 125 MHz): δ 161.1 (s), 150.3 (s), 147.6 (s), 145.0 (s),
144.3 (s), 135.0 (d), 128.2 (d), 127.9 (d), 126.1 (d), 122.0 (s); m/z
(MALDI-TOF) 267 (MH+ + 2, 75%), 266 (MH+ + 1, 25), 265
(MH+, 91), 245 (100), 192 (28), 150 (13), 120 (10).
7-Bromo-2-(4-chloro-1,2,5-thiadiazol-3-yl)quinazolin-4(3H)-one
(20d). Similar treatment (procedure C) of 7-bromo-4-chlorobenzo-
[e][1,2,6]thiadiazino[3,4-b][1,4]diazepin-10(11H)-one (34.4 mg,
0.100 mmol) with MeOH (4.5 mL) and glacial AcOH (0.50 mL)
gave after 3 d the title compound 20d (25.9 mg, 75%) as colorless
needles, mp (hotstage) 241−242 °C (DCE); Rf 0.22 (DCM); (Anal.
Calcd for C10H4BrClN4OS: C, 34.96; H, 1.17; N, 16.31. Found: C,
35.13; H, 1.13; N, 16.44); λmax(DCM)/nm 244 (log ε 4.49), 257
(4.31), 317 (4.28), 331 inf (4.21), 346 inf (3.92); νmax/cm−1 3284w
(N-H), 3080w and 3032w (C-H), 1672s, 1595m, 1557w, 1497w,
1454w, 1435m, 1416w, 1371w, 1327w, 1296w, 1252w, 1177m,
1138m, 1063w, 1047w, 930m, 901m, 887m, 880m, 866m, 858m,
1
845m, 785m; H NMR (DMSO-d6, 500 MHz): δ 12.96 (br s, 1H),
8.11 (d, 1H, J = 8.5 Hz), 8.00 (d, 1H, J = 1.9 Hz), 7.80 (dd, 1H, J =
8.5, 1.9 Hz); 13C{1H} NMR (DMSO-d6, 125 MHz): δ 160.9 (s),
150.1 (s), 148.8 (s), 146.4 (s), 144.5 (s), 131.1 (d), 130.0 (d), 125.5
(s), 128.2 (d), 121.2 (s); m/z (MALDI-TOF) 347 (MH+ + 4, 12%),
345 (MH+ + 2, 100), 343 (H+, 73).
2-(4-Phenyl-1,2,5-thiadiazol-3-yl)quinazolin-4(3H)-one (20e).
Similar treatment (procedure C) of 4-phenylbenzo[e][1,2,6]-
thiadiazino[3,4-b][1,4]diazepin-10(11H)-one (30.6 mg, 0.100
mmol) gave after 3 d the title compound 20e (22.3 mg, 73%) as
colorless plates, mp (hotstage) 176−177 °C (c-hexane); Rf 0.67
(DCM/t-BuOMe, 90:10); (Anal. Calcd for C16H10N4OS: C, 62.73;
H, 3.29; N, 18.29. Found: C, 62.84; H, 3.12; N, 18.15); λmax(DCM)/
nm 250 inf (log ε 4.20), 299 inf (4.07), 315 (4.17), 320 (4.13), 332
(4.12), 348 inf (3.88); νmax/cm−1 3204w (N-H), 1688m, 1676s,
1603m, 1562w, 1485w, 1468m, 1445m, 1335w, 1317w, 1306w,
Reaction of 4-Chlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]-
diazepin-10(11H)-one (4a) with MeOH/AcOH 90:10 (Table S3,
Entry 10) (Typical Procedure C). To a stirred mixture of MeOH (0.9
mL) and glacial AcOH (100 μL) at ca. 20 °C was added 4-
chlorobenzo[e][1,2,6]thiadiazino[3,4-b][1,4]diazepin-10(11H)-one
(4a) (26.5 mg, 0.100 mmol), and the mixture was heated to ca. 65 °C
until no starting material remained (TLC, 24 h). The reaction mixture
was left to cool to ca. 20 °C, then filtered, and the solid was washed
with MeOH (5 mL) and dried under vacuum to give 2-(4-chloro-
1,2,5-thiadiazol-3-yl)quinazo-lin-4(3H)-one (20a) (24.4 mg, 92%) as
colorless needles, mp (hotstage) 253−254 °C (DCE); Rf 0.35
1
1238w, 1144m, 926m, 897w, 747w, 797s, 754m, 745m, 729m; H
NMR (DMSO-d6, 500 MHz): δ 10.16 (br s, 1H), 8.32 (d, 1H, J = 7.8
Hz), 7.84 (d, 2H, J = 7.2 Hz), 7.73 (dd, 1H, J = 7.0, 7.0 Hz), 7.55−
7.48 (m, 5H); 13C{1H} NMR (DMSO-d6, 125 MHz): δ 162.7 (s),
161.2 (s), 150.9 (s), 147.8 (s), 144.5 (s), 134.9 (d), 132.6 (s), 130.3
(d), 129.9 (d), 128.6 (d), 128.2 (d), 127.8 (d), 126.7 (d), 122.2 (s);
m/z (MALDI-TOF) 308 (MH+ + 1, 16%), 307 (MH+, 100).
3,5-Dioxo-4,5-dihydro-3H-benzo[e][1,4]diazepine-2-carbonitrile
(28). To a stirred solution of 4-chlorobenzo[e][1,2,6]thiadiazino[3,4-
1
(DCM); H NMR (DMSO-d6, 500 MHz): δ 12.8 (br s, 1H), 8.21
(dd, 1H, J = 8.0, 1.3 Hz), 7.91 (ddd, 1H, J = 7.3, 7.3, 1.5 Hz), 7.80 (d,
1H, J = 8.0 Hz), 7.65 (ddd, 1H, J = 7.5, 7.5, 1.0 Hz); identical to that
reported above.
2-(4-Chloro-1,2,5-thiadiazol-3-yl)-6-methylquinazolin-4(3H)-one
(20b). Similar treatment (procedure C) of 4-chloro-8-methylbenzo-
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b][1,4]diazepin-10(11H)-one (4a) (26.5 mg, 0.100 mmol) in MeCN
(1 mL) at ca. 20 °C was added phenyliodine bis(trifluoroacetate)
(PIFA) (86 mg, 0.200 mmol), and the mixture was stirred at this
temperature until no starting material remained (TLC, 30 min). The
reaction mixture was then adsorbed onto silica and chromatographed
(DCM) to give the title compound 28 (11.8 mg, 59%) as colorless
needles, mp (hotstage) 221−222 °C (c-hexane/DCE); Rf 0.23
(DCM); (Anal. Calcd for C10H5N3O2: C, 60.31; H, 2.53; N, 21.10.
Found: C, 60.54; H, 2.62; N, 20.87); λmax(DCM)/nm 260 inf (log ε
3.36), 324 (3.42), 375 inf (2.73); νmax/cm−1 3223w (N-H), 3111w
(aryl C-H), 2247w (CN), 1678s (CO), 1620w, 1578w, 1562w,
1387m, 1323m, 1252m, 1211w, 1163w, 1134m, 1105w, 986w, 824m,
Biotronics Ltd. Furthermore, we thank the A. G. Leventis
Foundation for helping to establish the NMR facility at the
University of Cyprus.
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7.81 (dd, 1H, J = 7.8, 1.4 Hz), 7.78 (ddd, 1H, J = 7.8, 7.8, 1.4 Hz);
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00206.
■
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Accession Codes
CCDC 2052542−2052547 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Andreas S. Kalogirou − Department of Life Sciences, School of
Sciences, European University Cyprus, 1516 Nicosia, Cyprus;
orcid.org/0000-0002-5476-5805; Email: A.Kalogirou@
euc.ac.cy
Panayiotis A. Koutentis − Department of Chemistry,
University of Cyprus, 1678 Nicosia, Cyprus; orcid.org/
0000-0002-4652-7567; Email: koutenti@ucy.ac.cy
Author
Andreas Kourtellaris − Department of Chemistry, University
of Cyprus, 1678 Nicosia, Cyprus
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00206
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank I. J. Stavrou and C. P. Kapnissi-
Christodoulou for APCI+ mass spectra, the Cyprus Research
Promotion Foundation (Grants: ΣΤPAΤHII/0308/06,
NEKYP/0308/02 YΓEIA/0506/19 and ENIΣX/0308/83)
and the following organizations and companies in Cyprus for
generous donations of chemicals and glassware: the State
General Laboratory, the Agricultural Research Institute, the
Ministry of Agriculture, MedoChemie Ltd, Medisell Ltd, and
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