One-pot syntheses of dihydro benzo[b][1,4]thiazepines and -diazepines via coupling-isomerization-cyclocondensation sequences

Article abstract of DOI:10.1016/j.tet.2004.08.001

2,4-Di(hetero)aryl substituted 2,3-dihydro benzo[b][1,4]heteroazepines 7 and 9 (hetero=S, NH) can be readily synthesized in a one-pot process initiated by a coupling-isomerization sequence of an electron poor (hetero)aryl halide 4 and a terminal propargyl alcohol 5 subsequently followed by a cyclocondensation with 2-mercapto or 2-amino anilines 6 or 8, respectively. In addition, the structures were established unambiguously by an X-ray structure analysis of 9b. Graphical abstract.

Full text of DOI:10.1016/j.tet.2004.08.001

Tetrahedron 60 (2004) 9463–9469
One-pot syntheses of dihydro benzo[b][1,4]thiazepines
and -diazepines via
coupling–isomerization–cyclocondensation sequences
*
Roland U. Braun and Thomas J. J. Mu¨ller
¨
Organisch-Chemisches Institut der Ruprecht-Karls-Universitat Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany
Received 1 July 2004; revised 29 July 2004; accepted 2 August 2004
Dedicated to Professor Dr. Klaus Theodor Wanner on the occasion of his 50th birthday
Abstract—2,4-Di(hetero)aryl substituted 2,3-dihydro benzo[b][1,4]heteroazepines 7 and 9 (heteroZS, NH) can be readily synthesized in a
one-pot process initiated by a coupling–isomerization sequence of an electron poor (hetero)aryl halide 4 and a terminal propargyl alcohol 5
subsequently followed by a cyclocondensation with 2-mercapto or 2-amino anilines 6 or 8, respectively. In addition, the structures were
established unambiguously by an X-ray structure analysis of 9b.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
triple bond towards Michael-type additions, but also
stimulates the propargyl position, for example, towards an
alkyne–allene isomerization (Scheme 1).
Sequential transformations and multicomponent reactions
are steadily gaining a considerable academic, economic and
ecological interest since they address very fundamental
principles of synthetic efficiency and reaction design.1
Mastering unusual combinations of elementary organic
reactions under similar conditions is the major conceptual
challenge in engineering novel types of sequences. Tran-
sition metal catalyzed reactions with exceptionally mild
reaction conditions are of a paramount benefit if they can be
directed in a domino fashion generating a suitable reactive
functionality en route.2 Additionally, the prospect of
extending one-pot sequences into combinatorial and solid
phase syntheses1c,3 promises manifold opportunities for
developing novel lead structures of pharmaceuticals,
catalysts and even novel molecule based materials. As
part of our program designed to develop new multi-
component methodologies initiated by transition metal
catalyzed CC-bond formation, we have recently discovered
and developed an new mode of alkyne activation by a
detouring outcome of the Sonogashira coupling, that is, a
coupling–isomerization reaction (CIR).4 Conceptually, the
cross-coupling reaction of an electron deficient halide with a
terminal alkyne not only activates the newly formed internal
In particular, the Sonogashira coupling of electron poor
halides with 1-(hetero)aryl propargyl alcohols furnishes
chalcones in good to excellent yields. With this new enone
synthesis in hand and based upon the inherent bifunctional
electrophilicity of the in situ generated Michael acceptor as
a pivotal point, we have disclosed novel three- and four-
component syntheses of various heterocycles in the sense of
sequential one-pot reactions (Scheme 2).4–8h Here, we
report a facile one-pot synthesis of 2,4-di(hetero)aryl
substituted 2,3-dihydro benzo[b][1,4]diazepines and thiaze-
pines based upon a CIR sequence with a subsequent
cyclocondensation with 2-amino or 2-mercapto anilines.
2. Results and discussion
Dihydro benzodiazepines 1 and 2 (Fig. 1) constitute an
important class of psychopharmaca.9 In particular, deriva-
tives of dihydro benzo[b][1,4]diazepines 2 have aroused
considerable interest as CNS active anticonvulsant drugs,10
but also as in vitro non-nucleoside inhibitors of HIV-1
reverse transcriptase.11
Keywords: Catalysis; Cross-couplings; Cyclocondensations; Heterocycles;
Multicomponent reactions.
Besides these compounds, also the dihydro 1,4-benzothia-
zepines 3 (Fig. 1) have become increasingly interesting
since they show anti-fungal, anti-bacterial,12 anti-feedant,13
* Corresponding author. Tel.: C49-6221-546207; fax: C49-6221-546579;
e-mail: thomas_j.j.mueller@urz.uni-heidelberg.de
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.001

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R. U. Braun, T. J. J. Muller / Tetrahedron 60 (2004) 9463–9469
9464
Scheme 1. The coupling–isomerization-reaction (CIR) as a new mode of alkyne activation by cross-coupling.
anti-inflammatory, analgesic,14 and anti-convulsant15
activity. Furthermore, they can be oxidized to 1,4-
benzothiazepines under mild conditions.16
Our new CIR-chalcone synthesis (vide supra) opens a
straightforward convergent and modular access to 2,3-
dihydro benzo[b][1,4]heteroazepines in a one-pot fashion.
Thus, upon reacting electron poor (hetero)aryl halides 4 and
1-phenyl propynol (5a) under the reaction conditions of the
Sonogashira coupling in boiling mixture of triethylamine
Figure 1.
1
and THF and the subsequent addition of 2-amino thiophe-
nols 6 as suitable 1,4-dinucleophilic component and acetic
acid, the beige to yellow 2,3-dihydro benzo[b][1,4]thiaaze-
pines 7 were isolated in 38–85% yield (Scheme 3).
benzodiazepines 9 were unambiguously assigned by H,
13C, COSY, and NOESY NMR experiments. As a
consequence of the Michael addition–cyclocondensation
of the amino thiophenols and o-phenylene diamine to the
transient enone functionality three distinct aliphatic proton
resonances, a methine and two diastereotopic methylene
Likewise, the addition of ortho-phenylene diamine (8) after
the CIR of electron poor (hetero)aryl halides 4 and 1-aryl
propynol 5 furnishes the beige to yellow 2,3-dihydro
benzo[b][1,4]diazepines 9 in 39–79% yield (Scheme 4).
1
protons, appear most characteristically in the H spectra as
splitting patterns (doublets of doublets) of ABM spin
systems. Therefore, due to the characteristic geminal and
vicinal coupling constants (2JZ12.3–13.9 Hz, 3JZ4.3–
3
The structures of the benzothiazepines
7
and
4.9 Hz, JZ6.8–9.6 Hz) the signals at d 2.72–3.29 and d
Scheme 2. One-pot syntheses of heterocycles based upon a CIR sequence.

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R. U. Braun, T. J. J. Muller / Tetrahedron 60 (2004) 9463–9469
9465
Scheme 3. One-pot threecomponent synthesis of 2,3-dihydro benzo[b][1,4]thiazepines 7.
2.90–3.50 can be assigned to the diastereotopic methylene
protons. Conformation analyses applying the Karplus
correlation of coupling constants and dihedral angles
suggests that the thi- or diazepine core of the bicyclic
molecules only displays low conformational flexibility.
Furthermore, the appearance of vicinal coupling constants
(3JZ4.3–4.9 Hz, 3JZ6.5–9.6 Hz) for the signals at d 4.24–
5.84 completes the assignment of the methine resonances.
Furthermore, the signals of the (hetero)aromatic and
aliphatic protons can be detected with expected chemical
shifts.
Most indicatively, in the carbon NMR spectra the
quaternary carbonyl resonances of the imine carbon nuclei
are found between d 158.1–170.3. The methine and
methylene carbon nuclei resulting from the Michael
Scheme 4. One-pot threecomponent synthesis of 2,3-dihydro benzo[b][1,4]diazepines 9.

¨
R. U. Braun, T. J. J. Muller / Tetrahedron 60 (2004) 9463–9469
9466
addition appear at d 57.4–73.3 and d 35.1–37.4,
respectively.
sequence of electron poor (hetero)aryl halides, 1-aryl
propargyl alcohols, and 2-mercapto anilines or ortho-
phenylene diamine, respectively. Further studies to enhance
molecular diversity in pharmaceutically interesting targets
and extension to a combinatorial approach to 2,3-dihydro
benzo[b][1,4]heteroazepines are currently under
investigation.
Another strong spectroscopic support of benzoheteroaze-
pine formation can be derived from the mass spectra,
revealing that a benzyl and an a-cleavage (with respect to
the imine group) furnish the by far most dominant fragment
([M-Acc-p-CH]CH2]C). In the IR spectra typical CN-
valence vibrations of imines are found between 1604 and
1635 cmK1
.
3. Experimental
Furthermore, the structure of benzodiazepines 9 was
unambiguously corroborated by an X-ray crystal structure
analysis (Fig. 2) of compound 9b.17 The imine functionality
is almost fully conjugated with the anisyl substitutent and
the annealed benzo ring as clearly supported by dihedral
angles of 14.08 (C21–C16–C8–N2) and 2.38 (N2–C7–C6–
H6). Interestingly, the seven-membered ring adopts a chair/
twist conformation as indicated by the angle (33.28)
between the plane formed by C1–C8–C9 and the annealed
benzo ring.
All reactions involving water-sensitive compounds were
carried out in oven-dried Schlenk glassware under a
nitrogen atmosphere. The solvents were dried according to
standard procedures18 and were distilled prior to use.
Column chromatography: silica gel 60 M (mesh 230–400)
Macherey-Nagel or aluminium oxide 5016 A basic Fluka.
Thin layer chromatography (TLC): silica gel layered
aluminium foil (60 F254 Merck, Darmstadt) or aluminum
oxide layered aluminium foil (60 F254 Merck, Darmstadt).
Melting points (uncorrected): Bu¨chi Melting Point B-540.
The aryl propynols 5 were synthesized according to
literature procedures.19 Electron-poor (hetero)aryl halides
4, 2-mercapto anilines 6 and ortho-phenylene diamine (8)
were purchased from ACROS or Merck and used without
further purification. 1H and 13C NMR spectra: Bruker
ARX250, Bruker DRX 300, Bruker ARX 300, Varian VXR
400S, Bruker DRX500 or Bruker AC300 with CDCl3 as a
solvent. The assignments of quaternary C, CH, CH2 and
CH3 was made on the basis of DEPT spectra. IR: Bruker
Vector 22 FT-IR or Perkin Elmer Models Lambda 16. UV/
VIS: Hewlett Packard HP8452 A. MS: Finnigan MAT 90,
MAT 95 Q, Jeol JMS-700 and Finnigan TSQ 700.
Elemental analyses were carried out in the microanalytical
Although, several attempts were tested to expand the scope
of this facile coupling–condensation sequence to aliphatic
heteroazepines no satisfying results were obtained. Confor-
mationally flexible dinucleophiles like ethylene diamine or
cysteine methylester give rise to a complex mixture of
products, some of them are definitely aldol cleavage
products as detected by mass spectrometry and proton
NMR analysis. Structurally rigid aliphatic diamines such as
(R,R)-1,2-diamino cyclohexane react in analogy to ortho-
phenylene diamine according to NMR and mass spec-
trometryofthecrude product furnishinga singlediastereomer,
however, upon purification (column chromatography or
recrystallization from reasonably polar solvents) solvolysis
lead to the isolation of the chalcone precursor. Hence, at this
point the coupling–condensation sequence to heteroaze-
pines is restricted to the formation of benzo derivatives.
¨
laboratories of Department Chemie der Universitat
Mu¨nchen and the Organisch-Chemisches Institut der
¨
Universitat Heidelberg.
3.1. General procedure for the one-pot synthesis of
benzodiazepines and benzothiazepines
In conclusion, we have disclosed a straightforward con-
vergent and modular one-pot synthesis of 2,3-dihydro
benzo[b][1,4]thiazepines 7 and 2,3-dihydro benzo[b]
[1,4]diazepines 9 based upon a CIR–cyclocondensation
A magnetically stirred solution of 1.00 mmol of halogen
compound 4, 1.05 mmol of propargyl alcohol 5, 14 mg
(0.02 mmol) of Pd(PPh3)2Cl2, and 2 mg (0.01 mmol) of CuI
in 5 mL of degassed triethylamine under nitrogen was
heated to reflux temperature for 16 h (for experimental
details see Table 1). After cooling to room temperature a
solution of 1.1 mmol of a 2-amino thiophenol 6 and 1.6 mL
of acetic acid or 1.1 mmol of o-phenylene diamine (8) were
added and the reaction mixture was heated to reflux
temperature for the times indicated. After cooling 15 mL
of diethylether was added and the mixture was filtered (for
benzodiazepines 9). Then, the solvents were removed from
the filtrate in vacuo. For benzothiazepines 7 the reaction
mixture was poured into a saturated aqueous solution of
potassium carbonate. The aqueous phase was extracted with
diethylether and the combined organic layers were dried
with anhydrous sodium sulfate and filtered. The solvents
were removed in vacuo. Crude 7 and 9 were chromato-
graphed on silica gel and/or recrystallized to give the
analytically pure benzothiazepines 7 or benzodiazepines
9.
Figure 2. ORTEP-plot of benzodiazepine 9b.

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9467
Table 1. Experimental details of the one-pot synthesis of 2,3-dihydro benzo[b][1,4]thiazepines 7 and 2,3-dihydro benzo[b][1,4]diazepines 9
Aryl halide 4
Propargyl alcohol 5
Aniline 6/8
THF (mL)
NEt3 (mL)
Time (h)
Yield
249 mg (1.00 mmol) of 4a
249 mg (1.00 mmol) of 4a
182 mg (1.00 mmol) of 4b
182 mg (1.00 mmol) of 4b
182 mg (1.00 mmol) of 4c
195 mg (1.00 mmol) of 4db
249 mg (1.00 mmol) of 4a
249 mg (1.00 mmol) of 4a
182 mg (1.00 mmol) of 4b
182 mg (1.00 mmol) of 4c
164 mg (1.00 mmol) of 4e
139 mg (1.05 mmol) of 5a
139 mg (1.05 mmol) of 5a
139 mg (1.05 mmol) of 5a
139 mg (1.05 mmol) of 5a
139 mg (1.05 mmol) of 5a
139 mg (1.05 mmol) of 5a
139 mg (1.05 mmol) of 5a
162 mg (1.05 mmol) of 5b
139 mg (1.05 mmol) of 5a
139 mg (1.05 mmol) of 5a
139 mg (1.05 mmol) of 5a
137 mg (1.09 mmol) of 6a
253 mg (1.10 mmol) of 6ba
137 mg (1.09 mmol) of 6a
253 mg (1.10 mmol) of 6ba
137 mg (1.09 mmol) of 6a
137 mg (1.09 mmol) of 6a
119 mg (1.10 mmol) of 8
119 mg (1.10 mmol) of 8
119 mg (1.10 mmol) of 8
119 mg (1.10 mmol) of 8
119 mg (1.10 mmol) of 8
6.0
6.0
6.0
6.0
6.0
6.0
6.0
10
3.5
3.5
3.5
3.5
3.5
3.5
3.0
5.0
2.0
5.0
2.0
20
24
14
24
24
8.5
24
23
36
16
36
242 mg (67%) of 7a
242 mg (50%) of 7b
241 mg (71%) of 7c
307 mg (75%) of 7d
289 mg (85%) of 7e
120 mg (38%) of 7f
269 mg (52%) of 9a
163 mg (44%) of 9b
254 mg (79%) of 9c
125 mg (39%) of 9d
177 mg (58%) of 9e
3.0
10
3.0
a
As 3b hydrochloride.
As 1d hydrochloride.
b
1
3.1.1. 2-(4-Nitro-phenyl)-4-phenyl-2,3-dihydro-ben-
zo[b][1,4]thiazepine (7a). According to the standard
procedure and after chromatography on silica gel (petrol-
ether/ethyl acetate 4:1) and after recrystallization from
ethanol 7a was isolated as pale yellow needles, mp 185 8C
(181 8C).20 1H NMR (CDCl3, 300 MHz): d 3.09 (m, 1H),
3.40 (dd, JZ4.9, 12.8 Hz, 1H), 5.04 (dd, JZ4.8, 12.5 Hz,
1H), 7.26–7.20 (m, 1H), 7.62–7.45 (m, 8H), 8.18 (d, JZ
8.7 Hz, 2H). 13C NMR (CDCl3, 75 MHz): d 37.3 (CH2),
59.2 (CH), 122.3 (Cquat.), 124.2 (CH), 124.2 (Cquat.), 125.9
(CH), 126.4 (CH), 127.0 (CH), 127.9 (CH), 129.1 (CH),
130.6 (CH), 132.2 (CH), 135.1 (CH), 136.2 (Cquat.), 147.4
(Cquat.), 150.4 (Cquat.), 169.8 (Cquat.). EI MS (70 eV, m/z
(%)): 360 (MC, 7), 224 (14), 211 (MCKO2NC6H4CHCH2,
100). IR (KBr): n~ 1608 cmK1, 1596, 1574, 1517, 1452,
1348, 1320, 1245, 1214, 1110, 1024, 856, 827, 787, 748,
700, 689, 613, 484. UV/Vis (CHCl3): lmax (3) 264 nm
(25,800), 322 (8000). Anal. calcd for C21H16N2O2S (360.5):
C 69.77, H 4.48, N 7.77, S 8.90. Found: C 69.78, H 4.45, N
7.73, S 8.78.
193 8C. H NMR (CDCl3, 300 MHz): d 3.03 (m, 1H), 3.30
(dd, JZ4.9, 12.9 Hz, 1H), 4.97 (dd, JZ7.7, 12.6 Hz, 1H),
7.16 (dt, JZ1.4, 7.5 Hz, 1H), 7.32 (dd, JZ1.9, 7.8 Hz, 1H),
7.41 (d, JZ8.3 Hz, 2H), 7.61–7.46 (m, 7H), 8.04 (dd, JZ
1.4, 7.6 Hz, 2H). 13C NMR (CDCl3, 75 MHz): d 36.7 (CH2),
59.4 (CH), 111.3 (Cquat.), 118.3 (Cquat.), 121.6 (Cquat.), 125.2
(CH), 125.3 (CH), 126.6 (CH), 127.1 (CH), 128.6 (CH), 130.0
(CH), 131.0 (CH), 132.4 (CH), 134.7 (CH), 137.1 (Cquat.),
148.6 (Cquat.), 152.2 (Cquat.), 168.1 (Cquat.). EI MS (70 eV, m/z
(%)): 340 (MC, 8), 211 (MCKNCC6H4CHCH2, 100), 108
(C6H4SC, 15). IR (KBr): n~ 3054 cmK1, 2229, 1609, 1574,
1500, 1452, 1434, 1414, 1324, 1246, 1214, 1182, 1110, 1064,
1020, 834, 792, 761, 694, 563, 484, 454. UV/Vis (CHCl3):
lmax (3) 244 nm (28,700). Anal. calcd for C22H16N2S (340.5):
C 77.62, H 4.74, N 8.23, S 9.42. Found: C 77.48, H 4.76, N
8.26, S 9.52.
3.1.4. 2-(4-Cyanophenyl)-4-phenyl-7-trifluoromethyl-
2,3-dihydro-benzo[b][1,4]thiazepine (7d). According to
the standard procedure and after triturating with ethanol and
after recrystallization from ethanol 7d was isolated as a
colorless solid, mp 178–179 8C. 1H NMR (CDCl3,
300 MHz): d 3.08 (m, 1H), 3.45 (dd, JZ4.7, 12.9 Hz,
1H), 5.05 (dd, JZ4.6, 12.4 Hz, 1H), 7.39–7.48 (m, 3H),
7.55–7.65 (m, 5H), 7.72–7.78 (m, 2H), 8.12 (d, JZ7.2 Hz,
2H). 13C NMR (CDCl3, 75 MHz): d 37.3 (CH2), 59.6 (CH),
112.6 (Cquat.), 119.2 (Cquat.), 122.4 (q, JZ3.7 Hz, CH),
123.0 (q, JZ3.7 Hz, CH), 126.3 (q, JZ271.1 Hz Cquat.),
127.7 (CH), 128.1 (CH), 129.0 (CH), 132.5 (CH), 133.4
(Cquat.), 133.5 (CH), 133.6 (q, JZ29.1 Hz Cquat.), 136.2
(CH), 137.6 (Cquat.), 149.1 (Cquat.), 153.6 (Cquat.), 170.3
(Cquat.). EI MS (70 eV, m/z (%)): 408 (MC, 5), 292 (16), 279
3.1.2. 2-(4-Nitro-phenyl)-4-phenyl-7-trifluoromethyl-
2,3-dihydro-benzo[b][1,4]thiazepine (7b). According to
the standard procedure and after chromatography on silica
gel (petrolether/ethyl acetate 1:1) and after recrystallization
from ethanol 7a was isolated as a colorless solid, mp 166–
1
167 8C. H NMR (CDCl3, 300 MHz): d 3.13 (m, 1H), 3.50
(dd, JZ4.9, 13.1 Hz, 1H), 5.14 (dd, JZ4.3, 12.3 Hz, 1H),
7.46 (d, JZ9.1 Hz, 2H), 7.50–7.66 (m, 4H), 7.74–7.85 (m,
2H), 8.12–8.17 (m, 2H), 8.23 (d, JZ9.1 Hz, 2H). 13C NMR
(CDCl3, 75 MHz): d 36.8 (CH2), 59.5 (CH), 121.9 (q, JCF
Z
3.5 Hz, CH), 122.7 (q, JCFZ3.8 Hz, CH), 124.3 (CH), 126.3
(q, JZ271.1 Hz Cquat.), 127.0 (CH), 127.5 (CH), 128.1
(Cquat.), 128.5 (Cquat.), 128.6 (Cquat.), 128.9 (Cquat.), 129.0
(CH), 131.9 (CH), 135.7 (q, JZ29.1 Hz Cquat.), 135.3 (CH),
147.5 (Cquat.), 169.5 (Cquat.). EI MS (70 eV, m/z (%)): 428
(MC, 8), 292 (19), 279 (MCKO2NC6H4CHCH2, 100). IR
(KBr): n~ 1614 cmK1, 1576, 1522, 1407, 1348, 1331, 1256,
1201, 1169, 1131, 1084, 901, 700. UV/Vis (CHCl3): lmax (3)
268 (27,700) nm. Anal. calcd for C22H15F3N2O2S (428.5):
C 61.68, H 3.53, N 6.54. Found: C 61.40, H 3.67, N 6.40.
(MCKNCC6H4CHCH2, 100), IR (KBr): n~ 3062 cmK1
,
2230, 1611, 1576, 1502, 1452, 1407, 1331, 1304, 1256,
1202, 1169, 1125, 1082, 1021, 899, 830, 769, 755, 690, 563.
UV/Vis (CHCl3): lmax (3) 242 nm (25,200), 266 (21,200).
Anal. calcd for C23H15F3N2S (408.4): C 67.64, H 3.70, N
6.86. Found: C 67.62, H 3.42, N 6.84.
3.1.5. 2-(2-Cyanophenyl)-4-phenyl-2,3-dihydro-ben-
zo[b][1,4]thiazepine (7e). According to the standard
procedure and after triturating with ethanol and after
recrystallization from ethanol 7e was isolated as a beige
solid, mp 183–184 8C. 1H NMR (CDCl3, 300 MHz): d 2.95
(m, 1H), 3.44 (dd, JZ4.9, 12.9 Hz, 1H), 5.49 (dd, JZ4.9,
12.5 Hz, 1H), 7.17–7.23 (m, 1H), 7.34–7.41 (m, 2H), 7.48–
7.58 (m, 5H), 7.62–7.70 (m, 2H), 7.77 (d, JZ8.0 Hz, 1H),
3.1.3. 2-(4-Cyanophenyl)-4-phenyl-2,3-dihydro-ben-
zo[b][1,4]thiazepine (7c). According to the standard
procedure and after chromatography on silica gel (petrol-
ether/ethyl acetate 4:1) and after recrystallization from
ethanol 7c was isolated as pale yellow needles, mp 192–

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9468
8.19–8.22 (m, 2H). 13C NMR (CDCl3, 75 MHz): d 37.4
(CH2), 57.4 (CH), 109.9 (Cquat.), 117.4 (Cquat.), 122.4
(Cquat.), 125.8 (CH), 125.9 (CH), 127.4 (CH), 127.8 (CH),
128.2 (CH), 129.0 (CH), 130.3 (CH), 131.8 (CH), 132.7
(CH), 133.5 (CH), 135.0 (CH), 136.6 (Cquat.), 147.4 (Cquat.),
151.7 (Cquat.), 168.9 (Cquat.). EI MS (70 eV, m/z (%)) 340
(MC, 17), 338 (MCKH2, 17), 236 (MCKH2–NCC6HC4 ,
11), 224 (97), 211 (MCKNCC6H4CHCH2, 100), 108
(C6H4SC, 10). IR (KBr): n~ 3053 cmK1, 2220, 1612, 1598,
1575, 1478, 1451, 1320, 1259, 1244, 1214, 1064, 1024, 834,
796, 760, 744, 688, 559, 475. UV/Vis (CHCl3): lmax (3)
264 nm (18,200), 336 (4500). Anal. calcd for C22H16N2S
(340.4): C 77.62, H 4.74, N 8.23, S 9.42. Found: C 77.45, H
4.81, N 8.17, S 9.49.
(Cquat.), 147.5 (Cquat.), 151.6 (Cquat.), 161.6 (Cquat.), 166.3
(Cquat.). EI MS (70 eV, m/z (%)): 373 (MC, 85), 358 (MCK
CH3, 45), 266 (MCKC6H4OMe, 20), 224 (MCKO2NC6-
H4CHCH2, 100), 209 (C6H4N]CC6H4OMeC, 24), 181
(24), 133 (MeOC6H4CCHC2 , 32), 119 (MeOC6H4CC, 19),
77 (PhC, 13). IR (KBr): n~ 3372 cmK1, 3071, 2836, 1604,
1570, 1514, 1479, 1417, 1346, 1288, 1251, 1175, 1108,
1038, 855, 833, 756, 699, 628, 531. UV/Vis (CHCl3): lmax
(3) 275 nm (26,200), 351 (8800). Anal. calcd for
C22H19N3O3 (373.4): C 70.76, H 5.13, N 11.25. Found: C
70.58, H 5.19, N 11.40.
3.1.9. 2-(4-Cyanophenyl)-4-phenyl-2,3-dihydro-ben-
zo[b][1,4]diazepine (9c). According to the standard pro-
cedure and after chromatography on silica gel (petrolether/
ethyl acetate 3:1) and after recrystallization from isopropa-
3.1.6. 4-Phenyl-2-(4-pyridyl)-2,3-dihydro-benzo[b]
[1,4]thiazepine (7f). According to the standard procedure
and after chromatography on silica gel (petrolether/ethyl
acetate 4:1) and after recrystallization from ethanol 7f was
isolated as brown resin. 1H NMR (CDCl3, 300 MHz): d 2.72
(dd, JZ9.5, 13.7 Hz, 1H), 2.90 (dd, JZ5.4, 13.8 Hz, 1H),
4.24 (dd, JZ5.4, 9.6 Hz, 1H), 7.09–7.11 (m, 2H), 7.18–7.59
(m, 7H), 7.80–8.11 (m, 2H), 8.56 (br, 2H). 13C NMR
(CDCl3, 75 MHz): d 36.3 (CH2), 73.3 (CH), 119.8 (Cquat.),
127.3 (CH), 127.8 (CH), 128.3 (CH), 128.5 (CH), 129.1
(CH), 129.2 (CH), 129.7 (CH), 131.5 (CH), 137.3 (Cquat.),
143.0 (Cquat.), 147.6 (Cquat.), 149.0 (CH), 158.1 (Cquat.). EI
MS (70 eV, m/z (%)) 316 (MC, 2), 224 (100). EI HRMS
(70eV, m/z) calcd for C20H16N2S: 316.1034, found:
316.1047. IR (KBr): n~ 2924 cmK1, 1635, 1597, 1467,
1445, 1375, 1254, 1218, 1179, 1072, 992, 761, 690. UV/Vis
(CHCl3): lmax (3) 260 (15,800).
1
nol 9c was isolated as a beige solid, mp 183 8C. H NMR
(CDCl3, 300 MHz): d 3.06 (dd, JZ7.2, 13.4 Hz, 1H), 3.20
(dd, JZ4.4, 13.4 Hz, 1H), 3.74 (br, 1H), 5.34 (dd, JZ4.4,
7.2 Hz, 1H), 6.82–6.85 (m, 1H), 7.03–7.11 (m, 2H), 7.29–
7.41 (m, 4H), 7.52–7.59 (m, 4H), 7.68–7.71 (m, 2H). 13C
NMR (CDCl3, 75 MHz): d 36.7 (CH2), 70.6 (CH), 111.7
(Cquat.), 118.6 (Cquat.), 120.6 (CH), 122.0 (CH), 126.6 (CH),
126.8 (CH), 126.9 (CH), 128.4 (CH), 128.9 (CH), 130.4
(CH), 132.6 (CH), 137.7 (Cquat.), 138.7 (Cquat.), 149.6
(Cquat.), 155.9 (Cquat.), 166.9 (Cquat.). EI MS (70 eV, m/z
(%)): 323 (MC, 62), 308 (MCKNH, 23), 246 (MCKC6H5,
29), 221 (MCKNCC6H4, 28), 194 (MCKNCC6H4CHCH2,
100). IR (KBr): n~ 3058 cmK1, 2227, 1608, 1498, 1475,
1448, 1350, 1330, 1298, 1249, 1230, 1113, 1099, 833, 761,
693, 566. UV/Vis (CHCl3): lmax (3) 242 nm (23,022), 260
(19,200), 362 (4800). Anal. calcd for C22H17N3 (323.4): C
81.71, H 5.30, N 12.99. Found: C 81.42, H 5.24, N 12.83.
3.1.7. 2-(4-Nitrophenyl)-4-phenyl-2,3-dihydro-ben-
zo[b][1,4]diazepine (9a). According to the standard pro-
cedure and after chromatography on silica gel (petrolether/
ethyl acetate 5:1) and after recrystallization from ethanol 9a
was isolated as orange crystals, mp 189–190 8C (189–
190 8C).21 1H NMR (CDCl3, 300 MHz): d 3.10 (dd, JZ7.1,
13.5 Hz, 1H), 3.23 (dd, JZ4.4, 13.5 Hz, 1H), 3.78 (br, 1H,
NH), 5.41 (dd, JZ4.4, 7.0 Hz, 1H), 6.84–6.87 (m, 1H),
7.07–7.11 (m, 2H), 7.29–7.38 (m, 4H), 7.61 (d, JZ8.6 Hz,
2H), 7.70–7.73 (m, 2H), 8.14 (d, JZ8.7 Hz, 2H). 13C NMR
(CDCl3, 75 MHz): d 36.6 (CH2), 70.5 (CH), 120.7 (CH),
122.2 (CH), 124.0 (CH), 126.7 (CH), 126.8 (CH), 127.1
(CH), 128.4 (CH), 128.7 (CH), 130.4 (CH), 137.7 (Cquat.),
138.7 (Cquat.), 139.8 (Cquat.), 147.5 (Cquat.), 151.5 (Cquat.),
166.8 (Cquat.).
3.1.10. 2-(2-Cyanophenyl)-4-phenyl-2,3-dihydro-ben-
zo[b][1,4]diazepine (9d). According to the standard
procedure and after chromatography on silica gel (petrol-
ether/ethyl acetate 4:1) and after recrystallization from
ethanol 9d was isolated as a yellow orange solid, mp 161–
1
163 8C. H NMR (CDCl3, 300 MHz): d 3.19 (dd, JZ6.4,
13.5 Hz, 1H), 3.27 (dd, JZ4.6, 13.5 Hz, 1H), 3.81 (br, 1H,
NH), 5.84 (m, 1H), 6.89 (d, JZ6.8 Hz, 1H), 7.04–7.12 (m,
2H), 7.26–7.36 (m, 5H), 7.42–7.47 (m, 1H), 7.63 (d, JZ
7.6 Hz, 1H), 7.72 (d, JZ6.8 Hz, 2H), 7.87 (d, JZ8.0 Hz,
1H). 13C NMR (CDCl3, 75 MHz): d 35.7 (CH2), 68.6 (CH),
109.7 (Cquat.), 117.3 (Cquat.), 120.7 (CH), 122.0 (CH), 126.6
(CH), 126.8 (CH), 127.4 (CH), 128.1 (CH), 128.3 (CH),
128.9 (CH), 130.2 (CH), 132.9 (CH), 133.2 (CH), 138.0
(Cquat.), 138.7 (Cquat.), 139.7 (Cquat.), 148.4 (Cquat.), 166.9
(Cquat.). EI MS (70 eV, m/z (%)): 323 (MC, 25), 320 (MCK
H2–H, 100), 308 (MCKNH, 14), 246 (MCKPh, 22), 219
(MCKC6H4N2, 57), 194 (MCKNCC6H4CHCH2, 53). IR
(KBr): n~ 3064 cmK1, 2222, 1612, 1573, 1478, 1448, 1335,
1264, 1108, 858, 764, 693, 528. UV/Vis (CHCl3): lmax (3)
263 nm (20,300), 362 (27,900). Anal. calcd for C22H17N3
(323.4): C 81.71, H 5.30, N 12.99. Found: C 81.71, H 5.31,
N 12.88.
3.1.8. 4-(4-Methoxyphenyl)-2-(4-nitrophenyl)-2,3-dihy-
dro-benzo[b][1,4]diazepine (9b). According to the stan-
dard procedure and after chromatography on silica gel
(petrolether/ethyl acetate 3:1) and after recrystallization
from ethanol 9b was isolated as a yellow solid, mp 186–
187 8C (186–187 8C).22 1H NMR (CDCl3, 300 MHz): d 3.05
(dd, JZ6.8, 13.5 Hz, 1H), 3.19 (dd, JZ4.7, 13.5 Hz, 1H),
3.82 (s, 3H), 5.40 (dd, JZ4.7, 6.5 Hz, 1H), 6.82 (d, JZ
8.9 Hz, 2H), 6.83–6.86 (m, 1H), 7.05–7.09 (m, 2H), 7.31–
7.34 (m, 1H), 7.62 (d, JZ8.7 Hz, 2H), 7.67 (d, JZ8.9 Hz,
2H), 8.15 (d, JZ8.7 Hz, 2H). 13C NMR (CDCl3, 75 MHz):
d 36.2 (CH2), 55.4 (CH3), 70.7 (CH), 113.3 (Cquat.), 113.7
(CH), 120.8 (CH), 122.3 (CH), 124.0 (CH), 126.2 (CH),
127.1 (CH), 128.5 (CH), 128.6 (CH), 131.3 (Cquat.), 137.6
3.1.11.
4-Phenyl-2-(2-thiazolyl)-2,3-dihydro-ben-
zo[b][1,4]diazepine (9e). According to the standard pro-
cedure and after chromatography on silica gel (petrolether/
ethyl acetate 2:1) and after crystallization from isopropanol
9e was isolated as yellow resin. 1H NMR (CDCl3,

¨
R. U. Braun, T. J. J. Muller / Tetrahedron 60 (2004) 9463–9469
9469
Toxicol. 1989, 2, 1–69. (f) Bremner, J. B. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 9,
pp 183–189.
300 MHz): d 3.29 (dd, JZ4.8, 13.9 Hz, 1H), 3.30 (dd, JZ
5.7, 13.4 Hz, 1H), 5.67–5.71 (m, 1H), 6.87–6.90 (m, 1H),
7.03–7.13 (m, 3H), 7.25–7.34 (m, 4H), 7.70–7.75 (m, 3H).
13C NMR (CDCl3, 75 MHz): d 35.1 (CH2), 69.5 (CH), 119.1
(CH), 121.0 (CH), 122.5 (CH), 126.1 (CH), 126.6 (CH),
128.0 (CH), 128.1 (CH), 130.0 (CH), 136.7 (Cquat.), 138.4
(Cquat.), 140.6 (Cquat.), 142.6 (CH), 167.1 (Cquat.), 175.1
(Cquat.). EI MS (70 eV, m/z (%)): 305 (MC, 96), 303 (MCK
H2, 30), 228 (MCKC6H5, 20), 221 (MCKthiazolyl, 35)
194 (MCKthiazolylCHCH2, 100), 179 (C6H5C]NC6HC4 ,
22), 84 (thiazolylC, 69), 77 (C6HC5 , 14). EI HRMS (70eV,
m/z) calcd for C18H15N3S: 305.0993, found: 305.0988. IR
(KBr): n~ 3057 cmK1, 1609, 1569, 1496, 1473, 1445, 1345,
1314, 1293, 1256, 1226, 1180, 1139, 1111, 1054, 769, 753,
729, 691. UV/Vis (CHCl3): lmax (3) 254 nm (18,500), 352
(5200). Anal. calcd for C18H15N3S (305.4): C 70.79, H 4.95,
N 13.76, S 10.50. Found: C 70.47, H 5.21, N 12.97, S 10.19.
10. For synthetic and pharmacological studies, see e.g., (a) Zellou,
A.; Cherrah, Y.; Hassar, M.; Essassi, E.-M. Ann. Pharm. Fr.
1998, 56, 169–174. (b) Savelli, F.; Boido, A.; Mule, A.; Piu,
L.; Alamanni, M. C.; Pirisino, G.; Satta, M.; Peana, A.
Farmaco 1989, 44, 125–140. (c) Nawojski, A.; Nawrocka, W.;
Liszkiewicz, H. Pol. J. Pharmacol. Pharm. 1985, 37, 69–72.
(d) Wilimowski, M.; Orzechowsa-Juzwenko, K.; Barczynska,
J.; Kedzierska-Gozdzik, L.; Witkowska, M.; Wojewodzki, W.;
Dus, E.; Plawiak, T.; Gryska, J.; Maska, H. Pol. J. Pharmacol.
Pharm. 1983, 35, 89–102. (e) Srivastava, V. K.; Satsangi,
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11. For synthetic and pharmacological studies, see e.g., (a) Parker,
K. A.; Dermatakis, A. J. Org. Chem. 1997, 62, 4164–4167.
(b) Hargrave, K. D.; Schmidt, G.; Engel, W.; Austel, V. Patent
Application: US 91-650141 19910204. Patent Priority: US
89-340937 19890420; US 89-372728 19890628; US
89-438922 19891117; US 90-600554 19901019.
Acknowledgements
The financial support of the Deutsche Forschungsge-
meinschaft (Graduiertenkolleg 850), Fonds der Chemischen
12. (a) Mane, R. A.; Ingle, D. B. Indian J. Chem., Sect. B 1982,
21B, 973–974. (b) Jadhav, K. P.; Ingle, D. B. Indian J. Chem.,
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¨
¨
Industrie and the Dr.-Otto-Rohm Gedachtnisstiftung is
gratefully acknowledged. The authors wish to thank Dr.
Kurt Polborn for the X-ray structure analysis of compound
9b.
13. Reddy, R. J.; Ashok, D.; Sarma, P. N. Indian J. Chem., Sect. B
1993, 32B, 404–406.
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