Construction of a Polycyclic Conjugated System Containing a Dibenzazepine Moiety by Cationic Gold(I)-Catalyzed Cycloisomerization

Article abstract of DOI:10.1002/ejoc.201601147

A new π-conjugated system of nitrogen-containing polycyclic compounds was constructed by cationic Au^I-catalyzed cycloisomerization. Intramolecular reaction of 9-(2-alkynylphenyl)-9H-carbazole derivatives gave a variety of penta- and hexacyclic compounds possessing a dibenzazepine skeleton. The rigid carbazole structure was responsible for efficient 7-endo-dig cycloisomerization.

Full text of DOI:10.1002/ejoc.201601147

A Journal of
Accepted Article
Title: Construction of a Polycyclic Conjugated System Containing a Dibenzazepine
Moiety by Cationic Au(I)-Catalyzed Cycloisomerization
Authors: Mamoru Ito; Ryosuke Kawasaki; Kyalo Stephen Kanyiva; Takanori Shibata
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European Journal of Organic Chemistry
10.1002/ejoc.201601147
Construction of a Polycyclic Conjugated System Containing a Dibenzazepine Moiety by Cationic Au(I)-Catalyzed
Cycloisomerization
Mamoru Ito1, Ryosuke Kawasaki1, Kyalo Stephen Kanyiva2, and Takanori Shibata*1,3
1Department of Chemistry and Biochemistry, School of Advanced Science and Engineering
Waseda University, Shinjuku, Tokyo 169-8555, Japan
2International Center for Science and Engineering Programs (ICSEP)
Waseda University, Shinjuku, Tokyo 169-8555, Japan
3ACT-C, Japan Science and Technology Agency (JST)
4-1-8 Honcho Kawaguchi, Saitama, 332-0012, Japan
Short Text: The cationic gold(I)-catalyzed hydroarylation of 9-(2-alkynylphenyl)-9H-carbazole derivatives proceeds smoothly
to give a variety of dibenzazepine derivatives. The products are obtained in high yields (up to >99%) by using two different
reaction conditions. This methods are highly atom economical processes. Some products exhibit highly fluorescence.
Keywords: gold • cycloisomerization • dibenzazepine • polycyclic compounds
R
R
cationic Au(I) cat.
N
N
7-endo-dig selective
high atom efficiency
mild conditions
R = aryl, H
up to >99%
1
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European Journal of Organic Chemistry
10.1002/ejoc.201601147
DOI: ((will be filled in by the editorial staff))
Heterocycles
Construction of a Polycyclic Conjugated System Containing a
Dibenzazepine Moiety by Cationic Au(I)-Catalyzed Cycloisomerization
Mamoru Ito, Ryosuke Kawasaki, Kyalo Stephen Kanyiva, and Takanori Shibata*
Abstract:
containing polycyclic compounds was constructed by
cationic Au(I)-catalyzed cycloisomerization. An
A
new -conjugated system of nitrogen-
derivatives gave a variety of penta- and hexacyclic
compounds possessing a dibenzazepine skeleton. The rigid
carbazole structure was responsible for efficient 7-endo-dig
cycloisomerization.
intramolecular reaction of 9-(2-alkynylphenyl)-9H-carbazole
Introduction
1c).[4] Herein, we propose cycloisomerization as a new strategy for
construction of the dibenzazepine skeleton: the cycloisomerization
of 1,n-enynes provides a cyclic compound in excellent atom-
efficiency under relatively mild conditions.[5] In general, highly
electrophilic transition metals, especially Au and Pt catalysts, are
used for activation of the alkyne moiety. We also previously
reported Au(I)-catalyzed cycloisomerization of aromatic enynes for
the preparation of naphthalene derivatives.[6] Inspired by this
background, we envisioned that the 7-endo-dig selective
cycloisomerization of N-(2-alkynylphenyl)aniline derivatives could
provide dibenzazepine derivatives (Scheme 1d).
Dibenzazepine is an important skeleton for pharmaceuticals and is
found in many tricyclic antidepressant drugs.[1] For example, 5H-
dibenzo[b,f]azepine-5-carboxamide (Carbamazepine) is widely used
for the treatment of epilepsy. Various strategies have been
developed for construction of the dibenzazepine skeleton. Wagner-
Meerwein rearrangement of 9-hydroxymethyl-9,10-dihydroacridine
is a classical approach to the synthesis of dibenzazepines, but this
method requires a large amount of strong acid at high temperature.[2]
With regard to a catalytic approach,[3,4] a combination of Pd-
catalyzed Buchwald-Hartwig amination and Heck reaction provides
substituted dibenzazepine derivatives (Scheme 1a).[3b] Pd-catalyzed
double N-arylation was also reported, where multisubstituted
dibenzazepines are prepared from dibromides and primary amines
(Scheme 1b).[3c] Ring-closing metathesis of bis(2-vinylphenyl)amine
is another protocol for the preparation of dibenzazepines (Scheme
Scheme 1. Catalytic Synthesis of Dibenzazepine Derivatives.
(a) Pd-catalyzed condensation (ref. 3b)
Pd2dba3
DavePhos
NaOt-Bu
Cl
+
[]
Prof. Dr. T. Shibata*
dioxane
N
Br
H2N
Department of Chemistry and Biochemistry, School of
Advanced Science and Engineering
Waseda University
Shinjuku, Tokyo 169-8555, Japan
E-mail: tshibata@waseda.jp
110 °C
R2
R1
H
R2
R1
(b) Double N-arylation (ref. 3d)
Pd2dba3
DPEphos
CsCO3
Homepage: http://www.chem.waseda.ac.jp/shibata/
RNH2
+
toluene
120 °C
N
R
ACT-C,
Br Br
R2
R1
R1
R2
Japan Science and Technology Agency (JST)
4-1-8 Honcho Kawaguchi, Saitama, 332-0012, Japan
(c) Ring-closing metathesis (ref. 4)
M. Ito and R. Kawasaki
Hoveyda-Grubbs 2nd
toluene, 100 °C
Department of Chemistry and Biochemistry, School of
Advanced Science and Engineering
Waseda University
N
N
Me
Me
Shinjuku, Tokyo 169-8555, Japan
(d) Our proposal: cycloisomerization
R
Dr. Kyalo Stephen Kanyiva
International Center for Science and Engineering Programs
(ICSEP)
Waseda University
Shinjuku, Tokyo 169-8555, Japan
R
metal cat.
7-endo-dig
N
N
R'
R'
Supporting information for this article is available.
Results and Discussion
We first subjected triarylamine derivative 1 to cationic Au(I)-
catalyzed cycloisomerization under our previously reported
conditions,[6] but no reaction proceeded (eq 1 in Scheme 2). We
2
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European Journal of Organic Chemistry
10.1002/ejoc.201601147
Table 1: Screening of Reaction Conditions for 2a.
considered that the lower reactivity of compound 1 could be due to
free rotation of the phenyl group on the nitrogen atom, and designed
carbazole-based compound 2 (eq 2). We expected that this substrate
could offer two advantages. First, the planarity of carbazole would
increase the nucleophilicity of the C1 position by the resonance
effect of the nitrogen atom.[7] Second, the steric repulsion of
carbazole and alkyne group would break the resonance effect to the
alkyne, resulting in the increase of the electrophilicity of alkyne.
Moreover, from the synthetic point of view, many biologically
active compounds and functional materials contain the carbazole
skeleton.[8] In particular, high electroluminescence was recently
reported in the carbazole-containing tribenzazepine derivatives.[9]
p-Tol
p-Tol
catalyst + silver salt
(10 mol %)
N
N
DCE, temp., 24 h
2a
3a
entry
catalyst
silver salt
AgSbF6
AgOTf
temp. [°C]
yield [%]
90
1
2
AuCl(PPh3)
AuCl(PPh3)
AuCl(PPh3)
AuCl(PPh3)
AuCl(PPh3)
AuCl(PPh3)
80
80
88
Scheme 2. Design of Carbazole-Based Substrate.
3
AgBF4
None
80
80
60
40
r.t.
r.t.
r.t.
r.t.
12
trace
27
4
p-Tol
5
AgSbF6
AgSbF6
AuCl(PPh3) (10 mol %)
AgSbF6 (10 mol %)
6
14
(1)
NR
N
7
AuCl[P(4-CF3C6H4)3]
AuCl[P(4-CF3C6H4)3]
AuCl[P(C6F5)3]
AgSbF6
AgOTf
AgSbF6
AgOTf
58
DCE, 80 °C, 23 h
8
65
9
33
1 (p-Tol = 4-MeC6H4)
10
AuCl[P(C6F5)3]
42
R
R
R
1
cationic
gold(I) cat.
N
(2)
N
N
2
3
7-endo-dig
product
6-exo-dig
product
We chose p-tolyl-substituted alkyne 2a as a model substrate and
subjected it to the above conditions (entry 1 in Table 1).
Gratifyingly, compound 2a was completely consumed, and 7-endo-
dig product 3a was selectively obtained in a high yield of 90%.[10]
The structure of 3a was confirmed by single-crystal X-ray structure
analysis (Figure 1). The carbazole moiety showed planarity, and the
azepine skeleton was a saddle-shaped structure, as we expected.[11]
This selectivity was explained by stereoelectronic effect.[12] The
external Lewis acid (gold catalyst) coordinated to the alkyne moiety
to change the symmetry of LUMO, resulting in the allowance of the
endo attack of nucleophile. This type of cyclization, Electrophile-
Promoted Nucleophilic Cyclization (EPNC), have been used for
endo-dig selective cyclization.[13] In the screening of counter anions,
hexafluoroantimonate gave the best results (entries 1-3). Only a
trace amount of 3a was detected under silver salt-free conditions,
which means that the use of cationic Au(I) catalyst was essential for
this cycloisomerization (entry 4). The yield was significantly
decreased at a lower reaction temperature because of low conversion
(entries 5 and 6). When the reaction was performed with the use of
more electrophilic Au(I) catalysts, cycloisomerization proceeded
even at room temperature, and moderate yield was achieved with a
Au(I) catalyst possessing tris(4-trifluoromethylphenyl)phosphine as
a ligand (entries 7-10).[14]
Figure 1. ORTEP diagram of compound 3a (thermal ellipsoids
shown at 50% probability, CCDC1495449).
Under the reaction conditions in entry 1 of Table 1
(condition A), various alkynes were subjected to cationic Au(I)-
catalyzed cycloisomerization (Table 1). Sterically hindered
substrate 2b also gave cycloadduct 3b in good yield (entry 1).
The reaction of p-anisyl-substituted alkyne 2c went to
completion within 6 h, and the corresponding product 3c was
obtained almost quantitatively (entry 2). In addition to a
naphthyl group, heteroaryl groups could also be used as
substituents on the alkyne terminus, and pentacyclic compounds
3d-3f were obtained in high yield (entries 3-5). Terminal alkyne
2g was reactive, as expected, and the reaction proceeded
smoothly even at room temperature within 2 hours (entry 6).[15]
In contrast, the reaction of phenyl-substituted alkyne 2h
proceeded sluggishly under condition A, and the yield of 3h was
very low because of low conversion (entry 7). When a more
electrophilic Au(I) catalyst prepared from AuCl[P(C6F5)3] and
AgOTf was used (condition B), the reaction proceeded even at
room temperature to give 3h quantitatively within 3 hours (entry
3
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European Journal of Organic Chemistry
10.1002/ejoc.201601147
8).[16] m-Tolyl, m-anisyl- and p-biphenyl-substituted alkynes 2i,
2j, and 2k were also efficiently transformed into cycloadducts 3i,
3j, and 3k, respectively (entries 9-11). Condition B gave
products in high yield in the reaction of substrates 2l and 2m
possessing an electron-deficient aryl group on the alkyne
terminus (entries 12 and 13).
Scheme 3. Substrates Possessing Substituent(s) on the Carbazole
Ring.
p-Tol
condition A
N
MeO
p-Tol
p-Tol
Table 2: Scope of Substituents on the Alkyne Terminus.
2n
Condition A
R
R
AuCl(PPh3) (10 mol %)
AgSbF6 (10 mol %)
DCE, 80 °C, 24 h
N
+
N
(3)
MeO
N
N
MeO
Condition B
AuCl[P(C6F5)3] (10 mol %)
AgOTf (10 mol %)
DCE, rt, 3 h
3n
77%
3n'
ND
p-Tol
2
3
condition A
entry
R
condition
yield [%]
N
1
2
2-MeC6H4 (2b)
A
Aa
A
A
A
Ab
A
B
B
B
B
B
B
75 (3b)
4-MeOC6H4 (2c)
1-naphthyl (2d)
3-thienyl (2e)
2-thienyl (2f)
H (2g)
98 (3c)
92 (3d)
86 (3e)
91 (3f)
82 (3g)
20 (3h)
p-Tol
p-Tol
3
4
2o
(4)
N
+
N
5
6
7
Ph (2h)
8
Ph (2h)
>99 (3h)
86 (3i)
3o
88% (3/2)
3o'
9
3-MeC6H4 (2i)
3-MeOC6H4 (2j)
4-PhC6H4 (2k)
4-ClC6H4 (2l)
4-CF3C6H4 (2m)
p-Tol
p-Tol
10
11
12
13
93 (3j)
98 (3k)
85 (3l)
condition A
N
N
(5)
97 (3m)
a Reaction time was 6 h. b AgOTf was used in place of AgSbF6. The
reaction was conducted at rt for 2 h.
3p
<5%
2p
Next, we examined the reaction of substrates with substituent(s)
on the carbazole ring (Scheme 3). The reaction of 4-
methoxycarbazole-derived substrate 2n proceeded selectively to
give 3n in good yield, and regioisomer 3n’ could not be detected (eq
3).
A
reasonable explanation for this result is that
Finally, we examined the reaction of 2,3-naphthylene-tethered
substrate 2q (eq 6). Hexacyclic compound 3q, which has an
extended -conjugated system, was obtained in high yield.
cycloisomerization occurred preferentially at the electron-rich
benzene ring. In contrast, the reaction of 2o possessing a
benzo[c]carbazole skeleton provided an inseparable mixture of
regioisomers 3o and 3o’ in
a
high total yield (eq 4).[17]
Benzo[a]carbazole-based substrate 2p was ineffective, and only a
trace amount of cycloadduct 3p was detected (eq 5). One possible
reason for this low conversion is the steric repulsion of 3p.
Conclusions
We here described the efficient synthesis of nitrogen-containing
polycyclic compounds. The creation of a new -conjugated system
was achieved by cationic Au(I)-catalyzed 7-endo-dig selective
cycloisomerization of carbazole-based substrates along with the
construction of a dibenzazepine skeleton. Additional studies to
4
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European Journal of Organic Chemistry
10.1002/ejoc.201601147
[14] For selected examples of highly electrophilic Au catalysts, see: a) E.
Lee, T. Ryu, Y. Park, S. Park, P. H. Lee, Adv. Synth. Catal. 2013, 355,
1585–1596; b) S. Nonaka, K. Sugimoto, H. Ueda, H. Tokuyama, Adv.
Synth. Catal. 2016, 358, 380–385.
[15] AgOTf gave better yield (82%) than AgSbF6 (61%) in the reaction of
2g.
expand the substrate scope and to examine the photophysical
properties of these compounds are ongoing in our laboratory.
Acknowledgments
This work was supported by JST, ACT-C, Japan and Waseda
University Grant for Special Research Projects.
[16] The reaction using AuCl[P(4-CF3C6H4)3] also gave 3h in excellent
yield (98%), but it required 24 hours to be completed.
[17] The regioisomeric ratio was determined by 1H-NMR, but the
regioisomer 3o and 3o’ could not be assigned.
Keywords: Gold • Cycloisomerization • Dibenzazepine • Polycyclic
Compounds
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5
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