HETEROCYCLES

Communication | Special issue | Vol. 90, No. 1, 2015, pp. 85-88
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,* Yuki Fujiwara, Akifumi Maruyama, Mitsuhisa Maruyama, Shunji Ito, Masafumi Yasunami, Ryuji Yokoyama, and Noboru Morita

Department of Chemistry, Faculty of Science, Shinshu University, Asahi, Matsumoto 390-8621, 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 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 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%).

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 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.).

References

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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).
9. Selected data of compound 2: mp 208.0 – 210.0 °C (MeOH); 1H 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).
11. Selected data of compound 4: mp 139.0 – 140.0 °C (MeOH); 1H 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).
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