Title The Synthesis of Triazepine Derivatives

Author(s) Hokama, Kozo; Yogi, Seiichi; Higa, Matsutake; Tamaki,Kazuyoshi

Citation琉球大学理工学部紀要. 理学編 = Bulletin of Science &Engineering Division, University of Ryukyus. Mathematics &natural sciences(17): 39-42

Issue Date 1974-03

URL http://hdl.handle.net/20.500.12000/24623

Rights

Bull. sciences & Engineering Div., Univ. of the Ryukyus. ( Math. & Nat. Sci.) 39

The Synthesis Of Triazepine Derivatives

Kozo HoKAMA* Seiichi YoGI* Ma tsutake HIGA* Kazuyoshi TAMAKi*

Phenacylbromide ketazine (I) is obtained in good yield by the bromination

of acetophenone azine in methanol. The reactivity of (I) obtained from the

above method has rarely been studied in the literature, except the study

by one of the authors that the reaction of (I) with benzylamine in the

presence of triethylamine gives good yield of 5-benzyl-4, 6-dihydro-3, 7-

diphenyl-1,2, 5-triazepine.lJ In this paper, various triazepine derivatives

.BrC~ C~Br

~~H-H•C~ + R-~

I II

III Ilia : R = CH3 Illc : R = n-C4 H9

Illd : R = CH2 CH2 OH

have been obtained by the reaction of (I) with many kinds of amines.

1 . 0 Experiment and Results

We used a Hitachi R-24 spectrometer for the NMR measurment and a Hitachi RMU-6L

mass spectrometer for the measurment of mass spectra. The MS measurment

was done up to 80 eV of ionization potential by the direct sample injection method.

1 . 1 Materials

For amines, methylamine (40% aq. soln. ), ethylamine (70 % aq . soln.),

n-butylamine, ethanolamine, benzylamine and aniline, commercial reagents with

first grade were used without any purification.

The synthesis of phenacylbromide ketazine (I) : 23.6 g. of acetophenone

ketezine (0.1 mole) was added to 250 ml of methanol. While cooling this solution

with ice, a solution containing 32 g (0.2 mole) of bromine in 100 ml of methanol - ---------- - ·------ --------------···· ···-------------

Received October 31, 2.973

*Dept. of Chern., Sci . & Eng. Div ., Univ. of the Ryukyus

40 The Synthesis Of Triazepine Derivatives

was added dropwise to the above solution. The reaction mixture was stirred for

about two hours. After the reaction, it was filtered with suction. Then the

crystal with yellowish orange color, phenacylbromide ketazine (1) , was obtained. The

yield was 22.6g (57% yield). m.p. 151-152°C. Found : C, 48. 74; H, 3.36; N, 6.83

%. Calcd for C16H14N2 Brz: C, 48.76; H, 3.57; N, 7.11%.

MS:mje 392, 394. NMR spectrum (CDCI3 ): 4.63 ppm (4H, two methylen singlet)

1.2 The reaction of (I) with amines

The representative example of the reaction of (I) with amines is described

below with using methylamine. 3.94 g of (I) was dissolved in the mixed solvent

prepared with 40 ml of ethanol and 40 ml of benzene. 4.0 g of methylamine (40%

aq. soln.) was added to the solution of (I), the solution was refluxed for two hours.

After the reaction, the solvent was distilled out under the reduced pressure, and

then by cooling the remaining mixture a crystal was obtained. The crystal was

recrystallized from ethanol. Then 5-methyl-4, 6-dihydro-3, 7-diphenyl-1,2, 5-triazepine

(Ilia) was obtained in 62% yield. The m. p. of (Ilia) was 118-119°C and its NMR

spectrum gave a signal due to methylen proton in triazepine ring at 3.40 ppm and

a signal due toN-substituted methyl proton at 2.49 ppm. In addition, the structure

of (Ilia) is supported by the results of the elemental analysis and mass spectrometry.

In the same way, 5-ethy 1-4, 6-dihydro-3, 7-diphenyl-1 , 2, 5-triazepine (IIIb), 5-n­

butyl-4, 6-dihydro-3, 7-diphenyl-1, 2, 5-triazepine (IIIc) and 5-benzyl-4, 6-dihydro-

3,7-diphenyl-1, 2, 5-triazepine (IIId) were obtained by the reaction of (I) with

ethylamine, n-butylamine and benzylamine, respectively. The results are shown

in Table 1.

Table 1. Reaction of I with II.

··-·-·· · --·- -- -----·· ···----_______ , ______ __________ , __

. - --- --------

Analysis (%)

Found (Calcd) Yield Mp MW

R (%) co c) (mje) c H N --- -- -----------~~-- ·-· - -~------------

III a CH3 62 118-119 263 77.60 6.32 15.89 (77.53) (6.51) (15.96)

IIIb Cz Hs 52 134-135 277 78.06 6.76 15.29 (77.94) (6.91) (15.15)

IIIc n·C4 Hg 60 98-99 305 78.71 7.73 13.61 (78.65) (7.59) (13.76)

Illd HO·CHz CH2 36 129-130 293 73.99 6.55 14.25 (73.69) (6.53) (14.33)

IIIe Cs H5 CH2 51 121-122 339 81.71 6.21 12.29 (81.39) (6.24) (12.38)

- - ----------- ---------- - ----

Bull. Sciences & Engineering Div ., Univ. of the Ryukyus. (Math. & Nat. Sci.) 41

In the reaction of (I) with ethanolamine which has two active centers,

the dibromide is considered to react with amino group or hydroxy group, but the

product is 5-hydroxyethyl-4, 6-dihydro-3, 7-diphenyl-1,2, 5-triazepine (IIIe) by judging

from the results of NMR measurment, mass spectrometry and the elemental analysis.

NMR data of these triazepines are tabulated i:~. Table 2.

Table 2. NMR data of triazepines.

-------. · ·- ······-----------

Chemical shift (ppm) (CDC!s ) Compound

N-CH2 -C= N-CH2- N-C!!_2 -CH2 -CHJ - - --·---- -- ----- ------- --~------ --------------···

Ct; Hs CH3 3.40 s 2,49 s

c6 Hs C2 Hs 3.50 s 2.65m 1.20 t

C6 Hs n-C4 Hg 3.40 s 2,55 t 1.50m 0.98 t

c6 H6 HO-CH2CH2 3.64 s 2.88 t 3. 70 t

C6 Hs C6 Hs CH2 3.42 s 3. 70s

The triazepine derivatives were not obtained in the reaction of (I) with

ammonia and neither in the reaction of (I) with aniline. In the latter reaction a

substance like tar was produced.

As the different method from that mentioned above to synthesize (I), we

can introduce the synthesis by the reaction of phenacylbromide with hydrazine.

In order to attest the configurational identity of these two kinds of bromides (one

obtained by the bromination of acetophenone ketazine and another obtained by the

reaction of phenacylbromide with hydrazine), these two kinds of bromides were

tried to react with an amine under the same conditions.

In both the reactions, the same triazepine was obtained and the yield was almost

equal.

The NMR measurment for these two kinds of bromides also gave the same

results. From the above facts, these two kinds of bromides seem to give the same

configuration as follows:

42 The Synthesis Of Triazepine Derivatives

CH2 Br I

C6 Hs - C = 0 + NHz NHz

We wish to thank Prof. 0. Tsuge of Kyushu University for his invaluable advice for this work.

1). 0. Tsuge, M. Tashiro, K. Kamata, K. Hokama, Organic Preparations and

procedures, INT. 3 (6) 289·293 (1971 ).