Efficient synthesis of dibenzazepine lactams via a sequential Pd-catalyzed amination and aldol condensation reaction

Article abstract of DOI:10.1016/j.tetlet.2019.151536

A simple and efficient reaction was developed for the synthesis of dibenzazepine lactam derivatives. The core 7-membered azepine ring was formed by a stepwise sequence involving a palladium-catalyzed amination and an aldol condensation.

Full text of DOI:10.1016/j.tetlet.2019.151536

Journal Pre-proofs
Efficient Synthesis of Dibenzazepine Lactams via a Sequential Pd-Catalyzed
Amination and Aldol Condensation Reaction
Ha-Jeong Song, Eunyoung Yoon, Jung-Nyoung Heo
PII:
S0040-4039(19)31335-8
DOI:
https://doi.org/10.1016/j.tetlet.2019.151536
TETL 151536
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 November 2019
9 December 2019
16 December 2019
Please cite this article as: Song, H-J., Yoon, E., Heo, J-N., Efficient Synthesis of Dibenzazepine Lactams via a
Sequential Pd-Catalyzed Amination and Aldol Condensation Reaction, Tetrahedron Letters (2019), doi: https://
doi.org/10.1016/j.tetlet.2019.151536
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Efficient Synthesis of Dibenzazepine Lactams via a Sequential Pd-Catalyzed Amination
and Aldol Condensation Reaction
Ha-Jeong Song,†,‡ Eunyoung Yoon,† and Jung-Nyoung Heo†,‡,*
† Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology,
‡
141 Gajeong-ro, Daejeon 305-600 Republic of Korea, Graduate School of New Drug
Discovery and Development, Chungnam National University, 99 Daehak-ro, Daejeon 305-764
Republic of Korea
Abstract
O
O
Br
O
R2
N R1
N R1
R2
O
aldol
condensation
R3
amination
R4
N
R4
NHR3
A simple and efficient reaction was developed for the synthesis of dibenzazepine lactam
derivatives. The core 7-membered azepine ring was formed by a stepwise sequence involving
a palladium-catalyzed amination and an aldol condensation.
Keywords
Dibenzazepine; Pd-catalyzed amination; Aldol condensation; Polycyclic compound
Bioactive molecules possessing a dibenz[b,f]azepine scaffold play an important role in drug
discovery.1, 2 The unique tricyclic dibenzazepine ring system lies at the heart of a wide array of
constitutionally diverse compounds exhibiting profound therapeutic properties.3 This class of
dibenzazepines, which includes carbamazepine (1),4 oxcarbazepine (2),5 eslicarbazepine
acetates (3),6 trimipramine (4),7 and clozapine (5),8 show antimicrobial, antifungal, antioxidant,
antiepileptic, and anticonvulsant, as well as anticancer activities (Figure 1).

O
AcO
H2N
N
N
N
H2N
O
H2N
O
O
1
2
3
Carbamazepine ( )
Oxcarbazepine ( )
Eslicarbazepine acetate ( )
N
N
N
N
Cl
N
N
H
4
5
Clozapine ( )
Trimipramine ( )
Figure 1. Pharmaceutical and bioactive compounds possessing a dibenzazepine scaffold.
a. Previous works: one-pot reactions
aldol condensation and
metal-free etherification
Br
O
CN
CN
H
O
OH
6
7
8
O
R2
N R1
O
N R1
Br
O
Ullmann coupling and
aldol condensation
R2
H
O
R3
9
7
OH
R3
10
b. This work: sequential Pd-catalyzed amination and aldol condensation
O
O
Br
O
R2
R3
N R1
N R1
R2
O
N
R4
NHR3
11
12
R4
13
Scheme 1. Synthetic strategies for accessing dibenzazepine lactam analogues.
As part of our work for the construction of polycyclic compounds for inclusion in libraries,9 a

series of dibenzoxepines 8 were prepared via a one-pot aldol condensation and metal-free
etherification (Scheme 1a).9e In addition, we developed a highly efficient synthesis of
dibenzoxepine lactam 10 based on a one-pot Ullmann coupling reaction and an aldol
condensation.9f Inspired by these developments, we envision that the formation of more
challenging dibenzazepine lactam 13 could be achievable. However, the first attempt with 4-
aminoindolinone 11 and 2-bromobenzaldehyde 7 failed to provide any desired product,
presumably due to the rapid formation of the imine between the amine and aldehyde groups.
Instead, acetal-protected arylbromide 12 was selected as a coupling partner for the Pd-catalyzed
amination (Scheme 1b). Here, we present the first synthesis of dibenzazepine lactams from 4-
aminoisoindolin-1-ones.
Table 1. Optimization of Pd-catalyzed amination reaction conditionsa
O
O
N Me
N Me
Br
O
Pd, Ligand, Base
O
O
toluene, wave
150 oC, 20 min
HN
O
NH2
11a
12a
14a
Entry
1
2
3
4
5
6
7
8
Pd
Ligand
Base
Yield (%)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
DPEphos
Xantphos
Davephos
Cy-Johnphos
X-Phos
S-Phos
NaOtBu
K3PO4
27
29
6
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
80
86
57
39
77
50
58
28
88
92
49
33
59
PdCl2(CH3CN)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
9
10
11
12
13
14
15
16
DIOP
dppf
S-Phos
a Reaction conditions: Amino-isoindol-1-one (0.6 mmol), ArBr (0.5 mmol), Pd (3.0 mol %),
ligand (4.5 mol %), base (1.4 equiv), toluene (3.0 mL), microwave 150 oC, 20 min.
Based on our previous work on microwave-promoted palladium-catalyzed aminations of
arylhalides,10 we investigated the reaction of 4-amino-2-methylisoindolin-1-one (11a) with
arylbromide 12a in the presence of a Pd catalyst (Table 1).11 The reaction using Pd(OAc)2 in
combination with BINAP and NaOtBu in toluene gave 14a in a low yield (entry 1). Changing
the base dramatically impacted the yields. The catalytic system with K3PO4 and K2CO3

provided 14a in a low yield (entries 2 and 3), but a great improvement was observed with
Cs2CO3 in 80% yield (entry 4). Next, screening palladium sources revealed Pd2(dba)3 as the
most active catalyst, as it provided an 86% yield (entries 4 – 7). Although Pd2(dba)3 showed
slightly better result, we decided to use Pd(OAc)2 as the easy-to-handle catalyst. Furthermore,
we screened a wide range of phosphine ligands with Pd(OAc)2 as the catalyst (entries 8-15).
Among the tested ligands, biaryl-based X-Phos and S-Phos proved to be very effective,
providing 88% and 92% yields, respectively (entries 12 and 13). Additionally, the combination
of Pd2(dba)3 and S-Phos gave 14a in 59% yield.
O
O
R2
R3
R4
Br
O
N R1
Pd(OAc)2, S-Phos
Cs2CO3
N R1
R2
O
O
toluene, wave
150 C, 20 min
N
O
R4
NHR3
11a-d
12a-h
14a-k
O
O
O
O
N Me
O
N Me
N Me
O
N Me
O
O
O
HN
F
HN
O
HN
O
HN
O
Me
Cl
14a
14b
14c
14d
, 92%
O
, 93%
O
, 98%
O
, 98%
O
N Me
N Me
N Me
N Me
O
O
HN
HN
O
O
O
S
O
HN
HN
O
O
N
MeO
14e
OMe
14f
14g
14h
, 89%
, 64%
, 75%
, 60%
O
O
O
N PMB
N Me
O
N Me
O
Cl
O
O
O
HN
N
HN
Me
O
14i
14j
14k
, 50%
, 98%
, 45%

a
Scheme 2. Substrate scope for the Pd-catalyzed amination. Reaction conditions: Amino-
isoindol-1-one (0.6 mmol), ArBr (0.5 mmol), Pd(OAc)2 (3.0 mol %), S-Phos (4.5 mol %),
Cs2CO3 (1.4 equiv), toluene (3.0 mL), microwave 150 oC, 20 min.
With an effective catalytic system in hand (Pd(OAc)2, S-Phos, and Cs2CO3), we then explored
the scope of the amination reaction (Scheme 2). The coupling reactions of 11a with halo- or
methyl-substituted arylbromides 12b-d proceeded smoothly to provide corresponding products
14b-d in 93-98% yields. When highly electron-rich dimethoxyphenylbromide 12e was used,
the reaction was less effective, and 14e was obtained in 64% yield. This coupling reaction was
also expanded to naphthyl- and heteroaryl-bromides, including pyridine and thiophene
derivatives, which provided good to excellent yields. Interestingly, the 1-PMB-substituted
derivative of 4-aminoindolin-1-one provided desired product 14i in 98% yield. Substrate 4-(N-
methylamino)indolin-1-one 11c was compatible with this transformation, albeit giving 14j in
a 45% yield. Additionally, the use of 5-chloro-substituted 11d was well tolerated and provided
14k in good yield.
Table 2. Optimization of the reaction conditions for the base-mediated aldol condensationa
O
O
O
N Me
N Me
N Me
Base
p-TsOH
O
O
EtOH/H2O = 1:1
rt, 10 min
EtOH (0.05 M)
HN
HN
HN
H
O
quantitative
14a
15a
13a
Entry
1
2
3
Base (equiv)
Temp (oC)
70
Time (h)
Yield (%)
10% NaOH (3.0)
NaOtBu (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
Cs2CO3 (3.0)
K2CO3 (3.0)
2
2
4
12
12
12
10
56
34
98
98
98
70
reflux
reflux
reflux
reflux
4
5
6b
a Reaction conditions: aldehyde 15a (0.3 mmol), base (3 equiv), EtOH (6 mL). b The one-pot
reaction was proceeded directly from 14a without isolation of 15a (reaction conditions: 14a
(0.3 mmol), p-TsOH (1 equiv), EtOH/H2O (2.0 mL/2.0 mL), rt, 10 min, then K2CO3 (3 equiv),
EtOH (6.0 mL), reflux, 12 h)
Next, the removal of the acetal protecting groups was easily accomplished in quantitative yields
by using standard acidic conditions. The subsequent aldol cyclization was examined under
basic conditions (Table 2). Among the various inorganic bases screened, both K2CO3 and
Cs2CO3 afforded cyclic product 13a in an excellent yield. Then, we further investigated a one-
pot tandem process for the acetal deprotection and aldol condensation. Applying the conditions
reported for the acid/base-promoted aldol condensation reaction,9d 14a afforded expected

product 13a in yield compatible to that obtained when the two reactions are conducted
separately (Table 2, entry 6).
O
O
R2
R3
R4
N R1
p-TsOH, EtOH/H2O
rt, 10 min
R2
N R1
O
then K2CO3, EtOH
reflux, 12 h
N
N
R3
O
R4
14a-k
13a-k
O
O
O
O
N Me
N Me
N Me
N Me
HN
HN
Me
HN
HN
F
13b
Cl
13a
13c
13d
, 98%
, 98%
, 83%
O
, 99%
O
O
O
N Me
N Me
N Me
N Me
HN
HN
HN
HN
O
N
S
OMe
, 86%
MeO
13e
13f
13g
13h
, 98%
, 67%
, 44%
O
N PMB
O
N Me
N Me
Cl
HN
N
HN
Me
13i
13j
13k
, 98%
, 98%
, 65%
a
Scheme 3. Substrate scope for the one-pot aldol condensation. Reaction conditions: acetal
(0.3 mmol), p-TsOH (1 equiv), EtOH/H2O (2.0 mL/2.0 mL), rt, 10 min, then K2CO3 (3 equiv),
EtOH (6.0 mL), reflux, 12 h.

Under the optimized conditions for the one-pot deprotections/aldol condensation, the
intramolecular cyclization occurred smoothly to furnish the desired dibenzazepine lactams
(Scheme 3). When electron-rich methyl (13c) and dimethoxy (13e) groups were used, the
corresponding products were obtained in excellent yields. Electron-withdrawing substituents
including halogens (13b, 13d, and 13k) were well tolerated. In addition, heteroaryl substituents
(14f–h) also proved suitable, leading to heterodibenzazepine lactams 13f–h in reasonable to
good yields. Notably, N-PMB protected lactam 14i smoothly afforded corresponding
dibenzazepine lactam 13i in 98% yield. The cyclization of 14j with tertiary-methylamine
effectively gave 13j in 65% yield.
In summary, we have developed an efficient synthesis of dibenzazepine lactams via a Pd-
catalyzed amination of 4-amino-1-isoindolones with acetal-protected aryl bromides, followed
by a one-pot deprotection/aldol condensation. Biological evaluations of these derivatives for
pharmaceutical use are currently underway.
Acknowledgements
This work was supported by the KRICT [KK1932-20].
Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://
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Efficient Synthesis of Dibenzazepine Lactams via a Sequential Pd-Catalyzed Amination
and Aldol Condensation Reaction
Ha-Jeong Song,†,‡ Eunyoung Yoon,† and Jung-Nyoung Heo†,‡,*
† Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology,
‡
141 Gajeong-ro, Daejeon 305-600 Republic of Korea, Graduate School of New Drug
Discovery and Development, Chungnam National University, 99 Daehak-ro, Daejeon 305-764
Republic of Korea
Graphical Abstract

O
O
Br
O
R2
N R1
N R1
R2
O
aldol
condensation
R3
amination
R4
N
R4
NHR3
Ms. Ref. No.: TETL-D-19-01736
Title: Efficient Synthesis of Dibenzazepine Lactams via a Sequential Pd-
Catalyzed Amination and Aldol Condensation Reaction
Tetrahedron Letters
Highlights,
 Synthesis of novel dibenzazepine lactams via Pd-catalyzed amination and
aldol condensation
 Rapid approaches of Pd-catalyzed amination using microwave irradiation
 One-pot process for cyclization with sequential acetal deprotection/aldol
condensation
Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may
be considered as potential competing interests: