Unexpected cyclization of tritylamines promoted by copper salt through c-h and c-n bond cleavages to produce acridine derivatives

Article abstract of DOI:10.1002/chem.201404656

Herein, we demonstrate that tritylamines undergo an unprecedented copper-mediated cyclization involving the cleavages of two C-H bonds and one C-N bond to give 9-arylacridine derivatives. This kind of acridines is of interest due to their biological properties and their unique optical and electro- and photochemical properties. Some of obtained acridine derivatives exhibit intense fluorescence in the solid state.

Full text of DOI:10.1002/chem.201404656

DOI: 10.1002/chem.201404656
Communication
&
Synthetic Methods
Unexpected Cyclization of Tritylamines Promoted by Copper Salt
through CÀH and CÀN Bond Cleavages to Produce Acridine
Derivatives
Ryosuke Morioka,[a] Koji Hirano,[a] Tetsuya Satoh,*[a, b] and Masahiro Miura*[a]
Chem. Eur. J. 2014, 20, 12720 – 12724
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Communication
metal-catalyzed coupling reactions have been recently devel-
oped,[6] the present cyclization provides
a more simple,
Abstract: Herein, we demonstrate that tritylamines under-
go an unprecedented copper-mediated cyclization involv-
ing the cleavages of two CÀH bonds and one CÀN bond
to give 9-arylacridine derivatives. This kind of acridines is
of interest due to their biological properties and their
unique optical and electro- and photochemical properties.
Some of obtained acridine derivatives exhibit intense fluo-
rescence in the solid state.
straightforward route from readily available substrates.
Similar to our previous work,[2b] treatment of tritylamine (1a;
0.5 mmol) in the presence of [RhCl(cod)]2 (0.01 mmol) and Cu-
(OAc)2·H2O (1 mmol) in o-xylene (3 mL) at 1608C for 8 h under
N2 gave 9-phenyl-9H-fluoren-9-amine (3a) in 90% yield
(entry 1 in Table 1). Eliminating the rhodium catalyst dramati-
Table 1. Reaction of tritylamine (1a).[a]
The transition-metal-catalyzed CÀH bond-functionalization re-
actions have attracted much attention in organic-synthesis
field, because they enable to simplify synthetic routes to vari-
ous complex molecules.[1] Among a variety of potential CÀH
transformation reactions is the intramolecular dehydrogenative
cyclizations involving twofold CÀH bond cleavages. They are
highly useful for constructing fused polycyclic frameworks,
which are of interest for their application to various fine chemi-
cals.[2,3] As such an example, we recently reported that trityl-
amine undergoes dehydrogenative cyclization in the presence
of [RhCl(cod)]2 and Cu(OAc)2·H2O as catalyst and oxidant, re-
spectively, accompanied by amino-directed CÀH bond cleav-
age to produce 9-phenyl-9H-fluoren-9-amine in high yield
(route 1 in Scheme 1).[2b] In the course of our further study of
Entry
Cu salt [mmol]
Solvent
T [oC]
Yield [%][b]
2a
3a
4a
1[c]
2
3
4
5
6
7
8
Cu(OAc)2·H2O [1]
Cu(OAc)2·H2O [2]
–
CuCO3 [2]
Cu2O [2]
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
mesitylene
DMA
160
160
160
160
160
160
160
160
160
170
170
170
170
170
170
170
170
170
0 90
34 0
0 0
0 0
0 0
0
22
0
0
0
0
0
0
8
CuCl2 [2]
0 0
Cu(acac)2 [2]
Cu(OCOCF3)2 [2]
Cu(OAc)2 [2]
Cu(OAc)2 [2]
Cu(OAc)2 [2]
Cu(OAc)2 [2]
Cu(OAc)2 [2]
Cu(OAc)2 [2]
Cu(OAc)2 [3]
Cu(OAc)2 [0.5]
Cu(OAc)2 [0.1]
Cu(OAc)2 [0.5]
12 0
32 0
56 0
9
10[d]
11[d]
12[d]
13[d]
14[d]
15[d]
16[d]
17[d]
18[e]
70 (62) 0
1
tr
7
22 0
36 0
46 0
62 0
62 0
60 0
28 0
diglyme
o-C6H4Cl2
dodecane
mesitylene
mesitylene
mesitylene
mesitylene
0
tr
tr
1
tr
tr
72 (72) 0
Scheme 1. Dehydrogenative cyclization of tritylamine.
[a] Reaction conditions: 1a (0.5 mmol) and Cu salt in solvent (3 mL) under
N2 for 6–8 h, unless otherwise noted. [b] GC yield is based on the amount
of 1a used. Value in parentheses indicates yield after purification. [c] With
[RhCl(cod)]2 (0.01 mmol). [d] Under air (1 atm). [e] Under O2 (1 atm). tr=
traces.
the cyclizative coupling, we have discovered that treatment of
the same substrate in the absence of any rhodium catalyst
gives rise to an unexpected cyclization product, 9-phenylacry-
dine, accompanied by the cleavages of two CÀH bonds and
one CÀN bond (route 2 in Scheme 1). In this case, fluorene for-
mation was not detected at all. This new cyclization appears to
involve a mechanistically fascinating copper series of reactions.
9-Phenylacrydine derivatives are also an important class of
molecules because of their biological properties, such as DNA
intercalation and antitumor activities,[4] as well as their unique
optical and electro- and photochemical properties.[5] Although
various synthetic methods for acrydines through transition-
cally changed the cyclization mode. Thus, in the absence of
[RhCl(cod)]2, a mixture of 9-phenylacrydine (2a) and 2-methyl-
4,4-diphenyl-4H-3,1-benzoxazine (4a) was obtained with no
formation of 3a (entry 2).[7,8] Further elimination of the copper
salt resulted in the complete recovery of 1a (entry 3). Other
copper salts, such as CuCO3 (entry 4), Cu2O (entry 5), CuCl2
(entry 6), and Cu(acac)2 (acac=acetylacetonate, entry 7), were
ineffective or far less effective. Cu(OCOCF3)2 was as effective as
the acetate (entry 8). The use of anhydrous Cu(OAc)2 was
found to improve the yield of 2a up to 56% (entry 9). In this
case, formation of 4a was effectively suppressed (entry 9 vs. 2),
although the reason is obscure at the present stage. Moreover,
when the reaction was conducted under air upon gentle heat-
ing at reflux in mesitylene (bath temperature 1708C), 2a was
obtained in 70% yield along with a minuscule amount of 4a
(entry 10). In other solvents, such as N,N-dimethylacetamide
(DMA), diglyme, o-C6H4Cl2, and dodecane, the 2a yield de-
[a] R. Morioka, Dr. K. Hirano, Prof. Dr. T. Satoh, Prof. Dr. M. Miura
Department of Applied Chemistry
Faculty of Engineering, Osaka University
Suita, Osaka 565-0871 (Japan)
E-mail: satoh@chem.eng.osaka-u.ac.jp
miura@chem.eng.osaka-u.ac.jp
[b] Prof. Dr. T. Satoh
JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404656.
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creased (entries 11–14). Although increasing and decreasing
the amount of Cu(OAc)2 to 3 and 0.5 mmol did not affect the
result severely (entries 15 and 16), its further decrease to
0.1 mmol reduced the 2a yield to 28% (entry 17). Fortunately,
even with 0.5 mmol of copper salt, 2a was obtained in good
isolated yield by conducting the reaction under O2 (1 atm;
entry 18).
disubstituted 9-arylacridines 2b and c in 72 and 68% yield, re-
spectively (entries 1 and 2). Halogenated tritylamines 1d–f also
underwent the cyclization to give acridines 2d–f, although
prolonged reaction times were needed (entries 3–5). Even in
the reaction of 1 f, no other product could be detected by GC
and GC-MS, although the substrate was completely consumed.
Interestingly, the cyclization of a highly substituted substrate,
tris(3,5-dimethylphenyl)methylamine (1g), proceeded smoothly
under standard conditions to give 9-(3,5-dimethylphenyl)-
2,4,5,7-tetramethylacridine (2g) selectively (entry 6).
Under the optimized conditions, the cyclization of variously
substituted triarylmethylamines 1b–g was examined (Table 2).
Treatment of tris(4-methylphenyl)methylamine (1b) and tris(4-
methoxylphenyl)methylamine (1c) gave the corresponding 3,6-
Next, the reactions of unsymmetrically substituted triaryl-
methylamines were examined (Scheme 2). Treatment of (4-
chlorophenyl)bis(4-methylphenyl)methylamine (1h) under
Table 2. Reaction of triarylmethylamine 1.[a]
Entry
1
t [h]
Product, yield [%][b]
1
6
Scheme 2. Reactions of 1h and i.
2
6
standard conditions gave a mixture of cyclization products, 2h
and h’ (86:14, 66% total yield). This indicates that the CÀH
cleavage on the chloro-substituted phenyl ring preferably
takes place compared to the methyl-substituted rings, and
thus, some electronic control can intervene. In the reaction of
(1-naphthyl)diphenylmethylamine (1i), the phenyl groups were
involved in the cyclization in preference to the naphthyl
moiety (2i/2i’ 79:21), probably due to steric reasons. In con-
trast to triarylmethylamines, diphenyl(3-thienyl)methylamine
and 1,1-diphenylethylamine did not undergo the cyclization at
all. In these cases, these amines were completely consumed by
unidentified side reactions.
3[c]
20
4[c]
5[c]
6
18
20
6
A plausible mechanism for the cyclization of 1a is illustrated
in Scheme 3. Coordination of the amino function of 1a to
Cu(OAc)2 and subsequent cyclometalation take place to form
a five-membered intermediate A.[9] Thus formed A undergoes
oxidation of its copper center leading to reductive elimina-
tion[10] to give a four-membered intermediate B.[11] Then, two-
fold electrocyclic reactions B to C and C to D and successive
dehydrogenation in D take place to generate 2a.[12] Meanwhile,
4a may be formed through addition of AcOH toward the
common intermediate C and subsequent dehydrative cycliza-
tion.
Besides such an associative pathway (path a in Scheme 3) in-
volving CÀN bond formation step prior to CÀN bond cleavage,
it is possible that the reaction proceeds through a dissociative
pathway (path b in Scheme 3) through a CÀN bond cleavage/
[a] Reaction conditions: 1a (0.5 mmol), Cu(OAc)2 (0.5 mmol) in mesitylene
(3 mL) at 1708C under O2. [b] Isolated yield. [c] By using Cu(OAc)2
(2 mmol).
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the resulting products exhibit intense fluorescence in the solid
state.
Experimental Section
General procedure for the reaction of tritylamines 1: A mixture of
tritylamine 1 (0.5 mmol), Cu(OAc)2 (0.5 mmol, 91 mg), and dibenzyl
(ca. 40 mg) as internal standard was stirred in mesitylene (3.0 mL)
under O2 at 1708C for 6–20 h. GC and GC-MS analyses of the mix-
tures confirmed consumption of 1. After cooling, the reaction mix-
ture was extracted with ethyl acetate (40 mL) and ethylenediamine
(1 mL). The organic layer was washed with water three times
(40 mL), dried over Na2SO4, and concentrated in vacuo. The desired
product 2 was isolated by column chromatography on silica gel by
using n-hexane/ethyl acetate (10:1) as eluent. Further purification
by using preparative GPC was conducted, if necessary. Characteri-
zation data of products are summarized in the Supporting Informa-
tion.
Scheme 3. Possible pathways from 1a to 2a and 4a.
formation sequence. However, this latter could be excluded by
a crossover experiment. Thus, treatment of a mixture of 15N-la-
beled tritylamine (1a-15N) and unlabeled 1b under standard
conditions did not give any crossover products (Scheme 4).
Acknowledgements
We thank Prof. Dr. N. Tohnai, Osaka University, for fluorescence
quantum efficiency measurements. This work was partly sup-
ported by Grants-in-Aid from MEXT, JSPS, and JST, Japan.
Keywords: CÀH activation
·
copper
·
cyclization
·
dehydrogenation · nitrogen heterocycles
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Received: July 30, 2014
Published online on September 4, 2014
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