Double palladium-catalyzed synthesis of azepines

Article abstract of DOI:10.1055/s-0032-1317667

The synthesis of new 5H-pyridobenzazepine and 5H-dipyridoazepine compounds using as key step a palladium-catalyzed amination-cyclization reaction is reported. By choosing an appropriate combination of ligands and reactants under standardized reaction conditions, N- and S-tricyclic products can be prepared in one step from the appropriate stilbenes. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317667

LETTER
▌49
lDettoeruble Palladium-Catalyzed Synthesis of Azepines
Synthesis of Azepines
Nina Božinović, Igor Opsenica, Bogdan A. Šolaja*
Faculty of Chemistry, University of Belgrade, PO Box 51, Studentski trg 16, 11158 Belgrade, Serbia
Fax +3811163298953; E-mail: bsolaja@chem.bg.ac.rs
Received: 04.10.2012; Accepted after revision: 26.10.2012
pines,4 and acid-catalyzed rearrangement of 1-aryl-
indoles.7 In addition, a highly efficient Pd/ligand-con-
trolled selective synthesis of 5H-dibenz[b,f]azepines in
high yield using a two-step reaction sequence has been re-
Abstract: The synthesis of new 5H-pyridobenzazepine and 5H-di-
pyridoazepine compounds using as key step a palladium-catalyzed
amination–cyclization reaction is reported. By choosing an appro-
priate combination of ligands and reactants under standardized re-
action conditions, N- and S-tricyclic products can be prepared in ported.8 Thus, using a variety of phosphines, DavePhos
one step from the appropriate stilbenes.
was established as the most effective among the ligands
investigated for the synthesis of 1.
Key words: azepines, thiepines, palladium, double N- and S-aryla-
tion, fused heterocycles
Recently, a very interesting approach to the synthesis of
5H-dibenz[b,f]azepines was developed. It comprised the
reaction of three components, ortho-substituted aryl
iodides, o-bromoanilines, and norbornadiene in a palladi-
um-catalyzed reaction, followed by retro-Diels–Alder re-
action of the norbornadiene intermediate to afford the
corresponding iminostilbene products in good yields.9
The tricyclic 5H-dibenz[b,f]azepine (iminostilbene) core
1 is a pharmaceutically important subunit in tricyclic ther-
apeutic agents such as carbamazepine (2) and opipramol
(3, Figure 1). Carbamazepine (2), a member of tricyclic
antidepressant (TCA), was approved by the FDA in 1968
for treatment of complex partial, tonic-clonic, and mixed-
type seizures.1 Opipramol (3) is primarily used for the
treatment of generalized anxiety disorders.2 Most TCA act
as reuptake inhibitors of norepinephrine, serotonin, and
dopamine, but opipramol acts as a high-affinity σ-receptor
agonist with modest subclass selectivity.3
The palladium-catalyzed double N-arylation reaction has
been widely used for the construction of different hetero-
cyclic skeletons: carbazoles,10 thienopyrroles,11 indoles,12
and phenazines.13 On the other hand, very few examples
of double palladium-catalyzed amination reactions for the
formation of azepine ring system are known.14,15 The syn-
thesis of symmetric and unsymmetric analogues of antide-
pressant imipramine was investigated in the presence of
Pd(OAc)2/Xphos15a or PdII–XPhos precatalyst15b which
were recently developed by Buchwald and co-workers.16
The yields of synthesized 3,7-disubstituted imipramines
were moderate to good.
N
H
N
1
O
NH2
2
Herein, we report on the synthesis of new 5H-pyridoben-
zazepine and 5H-dipyridoazepine compounds using as the
key step a palladium-catalyzed amination–cyclization re-
action. We reasoned that co-operative ortho effects17
could be exploited to obtain stilbenes (Z)-8 and (Z)-9 with
good selectivity. To that end, the alcohol 418 was trans-
formed into its corresponding bromo derivative, which
was used for the preparation of phosphonium salt 5. On
N
(CH2)3
N
N
HO
3
Figure 1 Tricyclic therapeutic agents structurally related to 5H- the other hand, phosphonium salt 7 was prepared using a
dibenz[b,f]azepine (1)
similar reaction sequence starting from commercially
available 2-bromobenzaldehyde (Scheme 1). The Wittig
reaction of phosphonium salts with freshly prepared 4-
chloropyridine-3-carbaldehyde afforded the desired ex-
pected ethylene derivatives 8 and 9. The unstable 4-chlo-
ropyridine-3-carbaldehyde was always prepared
immediately before its use. After subsequent chromato-
graphic separation Z isomer 8 was obtained in 54% yield,
and corresponding E isomer in 12% yield.17 Structural
characterization of two separated isomers was achieved
There are several classical efficient synthetic routes avail-
able for the synthesis of the iminostilbene moiety:4 dehy-
drogenation
of
10,11-dihydrodibenz[b,f]azepines,5
dehydrobromination of 10-bromo-10,11-dihydrodi-
benz[b,f]azepines,4 Wagner–Meerwein rearrangement of
9-hydroxymethyl-9,10-dihydroacridine derivatives,6 de-
hydration of 10,11-dihydro-10-hydroxydibenz[b,f]aze-
1
by H NMR spectroscopy (see Supporting Information).
Stilbenes (Z,E)-9 were obtained in lower yields, but better
stereoselectivity of two geometric isomers [(Z)-9 and (E)-
9, 24:1] were observed (see Supporting Information). The
SYNLETT 2013, 24, 0049–0052
Advanced online publication: 27.11.2012
DOI: 10.1055/s-0032-1317667; Art ID: ST-2012-D0848-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

50
N. Božinović et al
LETTER
geometry of compound 9 could not be established by
NMR spectroscopy (C2 symmetric), however, its Z geom-
etry is proposed based on the high yield of the correspond-
ing product 14 in the Pd-catalyzed double amination
(87%, see Table 2). In the next step we carried out the pal-
ladium-catalyzed double amination reaction of 8 (Table
1).
It has been described19 that the appropriate ligand selec-
tion is the key for successful amination, and furthermore,
it was shown that dialkylbiarylphosphines provide espe-
cially active catalysts in this context. In this work, we
screened the ligands using Pd(OAc)2 (5 mol% with re-
spect to 8) as source of palladium and NaOt-Bu (2.8
equiv) as a base, in toluene at 100 °C. Using biaryl phos-
phane ligands, JohnPhos and SPhos (10 mol% with re-
spect to 8), we obtained comparable yields of 10 (Table 1,
entries 1 and 3), but XPhos afforded a significantly lower
yield of 10 (Table 1, entry 4). Unfortunately, the reaction
with dppf was inefficient (Table 1, entry 5). Higher load-
ings of the palladium source (10 mol% vs. 5 mol%) and
ligand (30 mol% vs. 10 mol%) did not appreciably affect
the yield (Table 1, entry 2 vs. entry 1).
Cl
Cl
1. Br3P, CH2Cl2, r.t.
2. Ph3P, PhMe, 110 °C
Br–
PPh3
OH
N
N
46%, 2 steps
4
5
Br
Br
1. NaBH4, MeOH, r.t.
2. Br3P, CH2Cl2, r.t.
3. Ph3P, PhMe, 110 °C
Br–
PPh3
O
60%, 3 steps
6
7
Br
Cl
Cl
1. MnO2, CH2Cl2, r.t.
2. 5 or 7, LDA
THF, r.t.
N
8, 54% (2 steps)
OH
Cl
Cl
N
4
N
N
9, 43% (2 steps)
Scheme 1 Synthesis of ethylene derivatives 8 and 9
After optimizing reaction conditions, the iminostilbene 8
and 9 were subjected to coupling reactions with various
amines. The desired azepines 10–17 were obtained in fair-
ly good yields (Table 2).
Table 1 Palladium-Catalyzed Double Amination Reactions of 8 un-
der Various Conditionsa,b
Finally, as an expansion of this study, we explored the
synthesis of thiepine derivatives (Table 3). Various meth-
ods have been reported in the literature to obtain thiepine
derivatives,20 but only one involves palladium-catalyzed
reactions.21 In our approach as a source of sulfur for C–S
bond formation we used potassium thioacetate. Interest-
ingly, no conversion was observed when 8 and 9 were
subjected to the same reaction conditions as for the syn-
thesis of the azepine analogues. However, when we re-
placed JohnPhos with dppf22 (ineffective in the amination
reaction above) the desired thiepines were isolated in 28%
and 31% yields, respectively (Table 3). To expand the
scope of the new methodology, and to increase the yields,
we explored microwave-heated double palladium-cata-
lyzed C–S bond formation. After several different reac-
tion parameters were explored, it was found that the
reaction time could be reduced to 90 minutes at 175 °C us-
ing the same Pd/ligand loadings. Additionally, the yields
of the desired compounds obtained using microwave-
accelerated protocol were higher (Table 3).
Cl
Br
Pd(OAc)2, L
NaOt-Bu
PhMe, 100 °C, 48 h
N
N
N
Me2N
NH2
8
Me2N
10
P(t-Bu)2
PCy2
R1
PPh2
PPh2
R1
Fe
JohnPhos
dppf
(L4)
R2
(L1)
R
1 = OMe, R2 = H
L2 (SPhos)
R
1 = R2 = i-Pr
L3 (XPhos)
Entry
Pd source (mol%)
Ligand (mol%)
Yield (%)
1
2
3
4
5
Pd (OAc)2 (5)
Pd (OAc)2 (10)
Pd (OAc)2 (5)
Pd (OAc)2 (5)
Pd (OAc)2 (5)
L1 (10)
L1 (30)
L2 (10)
L3 (10)
L4 (10)
81
78
81
19
0
To conclude, we have developed a simple and efficient
palladium-catalyzed method for the synthesis of azepine
derivatives.23 In addition, to the best of our knowledge, for
the first time this methodology has been applied to thi-
epine-core synthesis.24 Further studies on dibenzostilbene
cyclization, optimization of the reaction conditions, and
evaluation of medicinal importance of these compounds
are under way.
a Reaction conditions: Pd(OAc)2, L, amine (3 equiv), NaOt-Bu (2.8
equiv) in toluene at 100 °C for 48 h under argon atmosphere; isolated
yields.
b Reactions were monitored by TLC and GC–MS.
Synlett 2013, 24, 49–52
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Azepines
51
Table 2 Palladium-Catalyzed Double Amination Reactions of 8 and
9 with Various Aminesa,b
Table 3 Synthesis of Thiepine Derivatives
Cl
X
Pd(OAc)2 (5 mol%)
dppf (10 mol%)
KSAc, NaOt-Bu
Cl
X
Pd(OAc)2, JohnPhos
N
Y
N
Y
RNH2, NaOt-Bu
N
Y
S
N
R
PhMe
N
PhMe, 100 °C
Y
8: X = Br, Y = CH
9: X = Cl, Y = N
8: X = Br, Y = CH
9: X = Cl, Y = N
N
N
N
N
N
N
S
S
N
N
18 28%a (51%)b
19 31%a (49%)b
Me2N
Me2N
a Reaction conditions: Pd(OAc)2 (5 mol%), dppf (10 mol%), potassi-
um thioacetate (1 equiv), NaOt-Bu (1.2 equiv) in toluene at 70 °C for
1 h, and subsequently at 110 °C for 14 h under argon atmosphere; iso-
lated yields.
10c 81%
14d 87%
N
N
N
b Reaction conditions: Pd(OAc)2 (5 mol%), dppf (10 mol%), potassi-
um thioacetate (1.2 equiv), NaOt-Bu (1.2 equiv) in toluene at 175 °C
for 90 min (microwave) under argon atmosphere; isolated yields.
N
N
N
N
O
O
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11c 61%
15d 69%
N
N
N
N
N
Et2N
Et2N
12c 79%
16d 47%
N
N
N
N
N
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17d 54%
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a Reaction conditions: Pd(OAc)2 (5 mol%), JohnPhos (10 mol%),
amine (3 equiv), NaOt-Bu (2.8 equiv) in toluene at 100 °C under ar-
gon atmosphere; isolated yields.
b Reactions were monitored by TLC until all of the starting material
was consumed.
c Reaction time was 48 h.
d Reaction time was 24 h.
Acknowledgment
This research was supported by the Ministry of Education and Sci-
ence of Serbia (Grant No. 172008), and NATO’s Public Diplomacy
Division in the framework of Science for Peace project SfP983638.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
detailed experimental procedures and spectra for all isolated com-
pounds.SunpIgfpi
o
nr
rtSationuIfp
o
oirmgirtnat
References and Notes
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 49–52

52
N. Božinović et al
LETTER
6632. (e) Dong, S.-X.; Zhang, X.-G.; Liu, Q.; Tang, R.-Y.;
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r.t. for 5 min, aryl halide (1 equiv) and amine (3 equiv) were
added, the tube was returned under argon and capped. The
reaction mixture was heated with stirring to 100 °C for the
appropriate time. Products were purified by preparative
column chromatography.
N,N-Dimethyl-3-{(5H-pyrido[4,3-b][1]benzazepin-5-
yl}propan-1-amine (10)
Yield 81%; yellow oil. 1H NMR (500 MHz, CDCl3): δ = 8.35
(d, J = 5.5 Hz, 1 H), 8.17 (s, 1 H), 7.30–7.22 (m, 1 H), 7.05–
6.98 (m, 2 H), 6.94 (d, J = 8.5 Hz, 1 H), 6.81 (d, J = 5.5 Hz,
1 H), 6.74 (d, J = 11.5 Hz, 1 H), 6.60 (d, J = 11.5 Hz, 1 H),
3.80–3.73 (m, 2 H), 2.39–2.33 (m, 2 H), 2.15 (s, 6 H), 1.82–
1.70 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ = 158.8,
150.5, 150.1, 149.1, 134.1, 133.6, 129.5, 129.3, 129.2,
129.1, 124.1, 121.1, 114.7, 57.1, 48.2, 45.5, 25.4. IR (ATR):
3413, 3023, 2944, 2858, 2817, 2767, 1635, 1578, 1481,
1419, 1392, 1332, 1244, 1184, 1123, 1060, 919, 831, 794,
766 cm–1. ESI-HRMS (+): m/z = 280.18125 [M + H]+ (error:
1.51 ppm).
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(24) Procedure for the Microwave Pd-Catalyzed Synthesis of
Thiepines 18 and 19
A reaction tube containing a stirring bar was evacuated and
backfilled with argon. The tube was charged with Pd(OAc)2
(5 mol%), dppf (10 mol%), NaOt-Bu (1.2 equiv), aryl halide
(1 equiv), and KSAc (1.2 equiv) under argon. The flask was
capped with a rubber septum, and toluene was added. The
reaction mixture was heated in a Biotage Initiator 2.5
microwave at 175 °C for 90 min. After completion, the
reaction mixture was cooled to r.t., and the products were
purified by preparative column chromatography.
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(23) General Procedure for Pd-Catalyzed Synthesis of
Azepines
[1]Benzothiepino[3,2-c]pyridine (18)
Yield 51%; white solid; mp 80–82 °C. 1H NMR (500 MHz,
CDCl3): δ = 8.48–8.44 (m, 2 H), 7.48–7.44 (m, 1 H), 7.36–
7.28 (m, 3 H), 7.28–7.24 (m, 1 H), 7.13 (d, J = 12.5 Hz, 1 H),
6.99 (d, J = 12.5 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ =
149.9, 149.8, 144.7, 139.7, 136.1, 135.4, 133.0, 132.7,
130.4, 129.9, 129.7, 128.7, 126.3. IR (ATR): 3056, 3025,
2927, 2855, 1738, 1629, 1563, 1538, 1471, 1442, 1416,
1389, 1306, 1275, 1174, 1056, 885, 836 cm–1. ESI-HRMS
(+): m/z = 212.05209 [M + H]+ (error: –3.58 ppm).
A reaction tube containing a stirrer bar was evacuated and
backfilled with argon. The tube was then charged with
Pd(OAc)2 (5 mol%), JohnPhos (10 mol%), and NaOt-Bu
(2.8 equiv) under argon. Toluene was added. After stirring at
Synlett 2013, 24, 49–52
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