Synthesis of 2,6-diaminoazulenes by the snar reaction with cyclic amines

Article abstract of DOI:10.3987/COM-14-S(K)1

2-Amino-6-bromoazulene derivatives reacted with cyclic amines (pyrrolidine, piperidine and morpholine) under the sealed-tube conditions to afford the corresponding 2,6-diaminoazulenes in excellent yields.

Full text of DOI:10.3987/COM-14-S(K)1

HETEROCYCLES, Vol. 90, No. 1, 2015
85
HETEROCYCLES, Vol. 90, No. 1, 2015, pp. 85 - 88. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 8th January, 2014, Accepted, 30th January, 2014, Published online, 3rd February, 2014
DOI: 10.3987/COM-14-S(K)1
SYNTHESIS OF 2,6-DIAMINOAZULENES BY THE SNAr REACTION
WITH CYCLIC AMINES†
Taku Shoji,a,b* Yuki Fujiwara,a Akifumi Maruyama,a Mitsuhisa Maruyama,b
Shunji Ito,c Masafumi Yasunami (the late),d Ryuji Yokoyama,e and Noboru
Moritae
a
Department of Chemistry, Faculty of Science, Shinshu University, Matsumoto,
390-8621, Japan. E-mail: tshoji@shinshu-u.ac.jp
b
Department of Material Science, Graduate School of Science and Technology,
Shinshu University, Matsumoto, 390-8621, Japan
c
Graduate School of Science and Technology, Hirosaki University, Hirosaki
036-8561, Japan
d
Department of Chemical Biology and Applied Chemistry, College of
Engineering, Nihon University, Koriyama 963-8642, Japan
e
Department of Chemistry, Graduate School of Science, Tohoku University,
Sendai 980-8578, Japan
Abstract – 2-Amino-6-bromoazulene derivatives reacted with cyclic amines
(pyrrolidine, piperidine and morpholine) under the sealed-tube conditions to
afford the corresponding 2,6-diaminoazulenes in excellent yields.
Aromatic compounds with multiple-amino functional groups have been of great interest owing to their
potential applications in organic electronic devices, such as hole transport materials for organic
light-emitting diodes.1 Therefore, a large number of synthetic procedures for aromatic compounds with
multiple-amino groups were found in literatures.2
In the pioneering works of azulene chemistry by Nozoe et al., 2,6-diaminoazulenes were first synthesized
from an aminotropolone derivative, but the procedure requires a multistep reaction for the preparation of
the starting tropolone derivatives which are essential to the preparation of 2,6-diaminoazulenes with
different amino functions.3 They have also reported that the most promising intermediate, diethyl
2-amino-6-bromoazulene-1,3-dicarboxylate (1) that could be obtained much easier, does not react with
†
Dedicated to Professor Isao Kuwajima on the occasion of his 77th birthday

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HETEROCYCLES, Vol. 90, No. 1, 2015
amines to give the corresponding 2,6-diaminoazulenes, although the related diethyl
6-bromoazulene-1,3-dicarboxylate is easily reacted with amines to give the corresponding
6-aminoazulene derivatives.4 Difference of the reactivity at the 6-bromo groups is explained by the
enhancement of electron-density of 1 owing to the electron-donating 2-amino group at the 6-position.
Although we have reported an efficient preparation of 2- and 6-aminoazulene derivatives by utilizing
palladium-catalyzed amination of 2- and 6-haloazulenes with several amines under the
Hartwig–Buchwald conditions,5 the conditions has never been applied to the preparation of
diaminoazulene derivatives due to the low availability of 2,6-dihaloazulenes.6 Thus, the development of
an efficient and versatile preparation method for azulene derivatives with multiple-amino functional
groups is one of the remained subjects in azulene chemistry for the applications of the aminoazulene
derivatives to organic electronic materials. Recently, the sealed-tube conditions have been revealed by Li
et al. as a good expedient for the amination reaction with volatile amines to provide aromatic amines that
could not be obtained by the straightforward reaction.7 Thus, the amination reaction using the sealed-tube
conditions will open a new and efficient strategy for the preparation of azulene derivatives with
multiple-amino functional groups.
Herein, we describe novel synthetic procedures for 2,6-diaminoazulene derivatives 2−4 by the SNAr-type
amination reaction of 1 with cyclic amines (i.e., pyrrolidine, piperidine and morpholine) under the
sealed-tube conditions, and by three-step amination reaction of 1 involving a protection and deprotection
sequence of 2-amino group by trifluoroacetic anhydride.
The outline of synthetic pathways for 2,6-diaminoazulene derivatives is shown in Scheme 1. The reaction
conditions and yield of the products are summarized in Table 1. The reaction of 1 with cyclic amines (i.e.,
pyrrolidine, piperidine and morpholine) was examined under the sealed-tube conditions for the first time.8
The SNAr reaction of 1 with pyrrolidine at 130 °C in a sealed-tube and subsequent chromatographic
purification on silica gel afforded the presumed product 29 in 94% yield (Entry 1). Likewise, the reaction
of 1 with piperidine afforded 310 in 89% yield (Entry 2). The amination of 1 with morpholine under the
sealed-tube conditions gave 411 in 91% yield (Entry 3). Although Nozoe et al. have reported that these
amines do not react with 1 to afford the 2,6-diaminoazulenes,5 we found that they could be obtained by
the SNAr reaction under the sealed-tube conditions. The reaction of 1 with alkylamines (i.e.,
tert-butylamine, diethylamine, dibutylamine and diisopropylamine) was also examined under the same
conditions, but the compound 1 was recovered, quantitatively, in all cases. The amination of ethyl
2-amino-6-bromoazulene-1-carboxylate (8) was also investigated, but the reaction did not undergo at all
under the same conditions. Therefore, both high nucleophilicity of cyclic amines and
electron-withdrawing groups at the 1,3-positions on azulene ring are essential to accelerate this SNAr-type
reaction. To explore the milder reaction condition, 2-amino group of 1 was protected by trifluoroacetyl

HETEROCYCLES, Vol. 90, No. 1, 2015
87
group that exhibits high electron-withdrawing nature. The trifluoroamidation reaction of 1 was
established by using 3.0 equiv. of trifluoroacetic anhydride (TFAA) in the presence of excess pyridine as
a base to afford the N-protected product 5 in 95% yield. As expected, amination reaction at the 6-position
of 5 with cyclic amines was readily proceeded under much milder reaction conditions and short reaction
period. Reaction of 5 with piperidine and morpholine was achieved at room temperature within 30 min to
afford 6 and 7 in 60% and 81% yields, respectively, along with the deprotected 1 (Entries 5 and 6). The
generation of 1 should exhibits the competition of the SNAr and deprotection reactions in these cases. In
contrast, pyrrolidine reacted with 5 to give the deprotected-substitution product 2 in 74% yield, due to the
consequence of the successive SNAr and deprotection reactions in one-pot (Entry 4). These results should
be attributable to the higher nucleophilicity of pyrrolidine than that of piperidine and morpholine.12
Deprotection of N-trifluoroacetyl group of 6 and 7 was readily established by the treatment with K2CO3 in
EtOH to give the corresponding 2,6-diaminoazulenes 3 and 4, quantitatively (6: 99%, 7: 99%).
CO2Et
Amines
K2CO3
H, reflux
R2N
NH2
130 °C
in sealed-tube
EtO
CO2Et
2: R2N = pyrrolidinyl
3
: R2N = piperidinyl
4
: R2N = morpholinyl
CO2Et
NH2
CO2Et
CO2Et
NHCOCF3
CO2Et
CO2Et
3.0eq. TFAA
6.0 eq. pyridine
Amines
Br
R2N
Br
NHCOCF3
CHCl3, reflux
room temperature
1
5
CO2Et
6: R2N = piperidinyl
7: R2N = morpholinyl
CO2Et
NH2
100% H3PO4
100°C
Amines
no reaction
Br
130 °C
in sealed-tube
8
Scheme 1. Synthesis of 2,6-diaminoazulene derivatives
Table 1. Reaction of 2-amino-6-bromoazulenes 1 and 5 with cyclic amines
Entry
Substrate
Amine
Reaction time [h]
6
6
6
0.5
0.5
0.5
Product, Yield [%]
2, 94
3, 89
1
2
3
4
5
6
1
1
1
5
5
5
pyrrolidine
piperidine
morpholine
pyrrolidine
piperidine
morpholine
4, 91
2, 74 and 1, 23
6, 60 and 1, 34
7, 81 and 1, 15
In conclusion, three new 2,6-diaminoazulene derivatives 2−4 have been prepared by the SNAr reaction of
compound 1 with cyclic amines under the sealed-tube conditions. Although a protection-deprotection

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sequence was required, 2,6-diaminoazulene derivatives 2−4 were also obtained from 1 under much milder
reaction conditions. Since compound 1 is readily available as a starting material by the selective
bromination of diethyl 2-aminoazulene-1,3-dicarboxylate at the 6-position, our synthetic methodologies
have potentials to be an efficient procedure for the synthesis of azulene derivatives with multiple-amino
functional groups.
ACKNOWLEDGEMENTS
This work was partially supported by a Grant-in-Aid for Research from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan (Grant No. 25810019 to T. S.).
REFERENCE AND NOTE
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8. General procedure: The solution of 1 (366 mg, 1.00 mmol) in the corresponding amines (5 mL)
was stirred at 130 °C in a sealed-tube for 6 h under an Ar atmosphere. The reaction mixture was
poured into a 1M HCl solution and extracted with CH2Cl2. The organic layer was washed with brine,
dried with Na2SO4, and concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel with CH2Cl2 to give 2,6-diaminoazulenes 2−4 (yield of the products is
summarized in Table 1).
1
9. Selected data of compound 2: mp 208.0 – 210.0 °C (MeOH); H NMR (500 MHz, CDCl3): δH =
9.01 (d, 2H, J = 11.7 Hz, 4,8-H), 7.05 (br s, 2H, NH2), 6.87 (d, 2H, J = 11.7 Hz, 5,7-H), 4.42 (q, 4H,
J = 7.2 Hz, CO2Et), 3.53 (t, 4H, J = 6.3 Hz, 2,5-H of pyrrolidine), 2.13 (t, 4H, J = 6.3 Hz, 3,4-H of
pyrrolidine), 1.45 (t, 6H, J = 7.2 Hz, CO2Et).
10. Selected data of compound 3: Orange oil; 1H NMR (500 MHz, CDCl3): δH = 8.97 (d, 2H, J = 11.8
Hz, 4,8-H), 7.32 (br s, 2H, NH2), 7.12 (d, 2H, J = 11.8 Hz, 5,7-H), 4.42 (q, 4H, J = 7.2 Hz, CO2Et),
3.49 (t, 4H, J = 5.5 Hz, 2,6-H of piperidine), 1.72 (br s, 6H, 3,4,5-H of piperidine), 1.45 (t, 6H, J =
7.2 Hz, CO2Et).
1
11. Selected data of compound 4: mp 139.0 – 140.0 °C (MeOH); H NMR (500 MHz, CDCl3): δH =
9.02 (d, 2H, J = 11.8 Hz, 4,8-H), 7.40 (br s, 2H, NH2), 7.15 (d, 2H, J = 11.8 Hz, 5,7-H), 4.43 (q, 4H,
J = 7.2 Hz, CO2Et), 3.88 (t, 4H, J = 4.9 Hz, 3,5-H of morpholine), 3.43 (t, 4H, J = 4.9 Hz, 2,6-H of
morpholine), 1.45 (t, 6H, J = 7.2 Hz, CO2Et).
12. T. Kanzian, T. A. Nigst, A. Maier, S. Pichl, and H. Mayr, Eur. J. Org. Chem., 2009, 6379.