Efficient synthesis of 1,3,5-benzotriazocines from tetrachloro-2-aza-1,3- dienes

Article abstract of DOI:10.1080/00397911.2013.836538

Easily accessible 1-aryl-2-aza-1,3-butadienes undergo a regioselective cyclocondensation with 2-(aminomethyl)aniline, giving rise to 1,3,5-benzotriazocines in good yields. The structure of the title compounds was proved with the aid of ¹H and ¹³C NMR spectra and, in one case, single-crystal x-ray analysis. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.836538

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Efficient Synthesis of 1,3,5-
Benzotriazocines from Tetrachloro-2-
aza-1,3-dienes
Roman Y. Vasylyshyn a , Bogdan A. Demydchuk a , Eduard B. Rusanov
b & Vladimir S. Brovarets a
a Institute of Bioorganic Chemistry and Petrochemistry, National
Academy of Sciences of Ukraine , Kyiv , Ukraine
b Institute of Organic Chemistry, National Academy of Sciences of
Ukraine , Kyiv , Ukraine
Accepted author version posted online: 28 Oct 2013.Published
online: 27 Dec 2013.
To cite this article: Roman Y. Vasylyshyn , Bogdan A. Demydchuk , Eduard B. Rusanov & Vladimir S.
Brovarets (2014) Efficient Synthesis of 1,3,5-Benzotriazocines from Tetrachloro-2-aza-1,3-dienes,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:5, 714-719, DOI: 10.1080/00397911.2013.836538
To link to this article: http://dx.doi.org/10.1080/00397911.2013.836538
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Synthetic Communications1, 44: 714–719, 2014
Copyright # IBOPC NAS Ukraine
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.836538
EFFICIENT SYNTHESIS OF 1,3,5-BENZOTRIAZOCINES
FROM TETRACHLORO-2-AZA-1,3-DIENES
Roman Y. Vasylyshyn,1 Bogdan A. Demydchuk,1
Eduard B. Rusanov,2 and Vladimir S. Brovarets1
1Institute of Bioorganic Chemistry and Petrochemistry, National Academy of
Sciences of Ukraine, Kyiv, Ukraine
2Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
Kyiv, Ukraine
GRAPHICAL ABSTRACT
Abstract Easily accessible 1-aryl-2-aza-1,3-butadienes undergo a regioselective cyclocon-
densation with 2-(aminomethyl)aniline, giving rise to 1,3,5-benzotriazocines in good yields.
1
The structure of the title compounds was proved with the aid of H and 13C NMR spectra
and, in one case, single-crystal x-ray analysis.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords 2-(Aminomethyl)aniline; 1,3,5-benzotriazocine; heterocyclization; regio-
selective cyclocondensation; tetrachloro-2-aza-1,3-dienes
INTRODUCTON
1,3,5-Triazocines are a little explored class of heterocycles. To our knowledge
there is only one report in the literature[1] on the synthesis of a 1,3,5-triazocine
derivative that exhibited biological activity as a blood platelet aggregation inhibitor.
Therefore, the development of novel synthetic approaches to the triazocine ring is of
importance for medicinal chemistry and drug discovery.
In this context our attention was drawn by two reports showing that chlori-
nated 2-aza-1,3-dienes of type A (Scheme 1), in which two electrophilic units have
remarkably different reactivity, undergo cyclocondensations with N-nucleophiles
Received August 6, 2013.
Address correspondence to Bogdan A. Demydchuk, Institute of Bioorganic Chemistry and
Petrochemistry, National Academy of Sciences of Ukraine, Murmanskaya St. 1, 02660 Kyiv, Ukraine.
E-mail: bogdem@mail.com
714

SYNTHESIS OF 1,3,5-BENZOTRIAZOCINES
715
Scheme 1. Cyclocondensations of chlorinated 2-aza-1,3-dienes with N-nucleophiles.
Scheme 2. Synthesis of 1,3,5-benzotriazocines from tetrachloro-2-aza-1,3-dienes.

716
R. Y. VASYLYSHYN ET AL.
of type B.[2,3] As depicted in Scheme 1, the first step was the condensation at the
more reactive electrophilic center of A, resulting in an intermediate C. The pro-
totropic equilibrium between structures C and D activated the second electrophilic
center to complete the cyclocondensation, yielding E.
1-Aryl-1,3,4,4-tetrachloro-4-aza-1,3-butadienes 1 (Scheme 2) were mainly used
as structure A. These are easily prepared through an addition of aromatic amides to
chloral.[4] Structure B was aromatic amines,[5] hydrazine derivatives and benzami-
dine,[6] and aminoazoles with an amidine unit.[7] However, in many cases the cyclo-
condensations proceeded in a nonregioselective manner, giving barely separable
mixtures of products. At the same time, the regioselectivity was observed when two
nucleophilic centers of structure B differed considerably in reactivity. The use of such
ambivalent nucleophiles resulted in efficient syntheses of 7-, 8-, and 9-membered rings
of type E.[8] In the present work we describe an efficient synthesis of several represen-
tatives of the 1,3,5-triazocine system through a regioselective cyclocondensation of
1-aryl-2-aza-1,3-butadienes 1 (Scheme 2) with 2-(aminomethyl)aniline.
The selectivity of the cyclization shown in Scheme 2 is seemingly due to the
interplay of electrophilic and nucleophilic pairs. Thus, a noticeably greater nucleo-
philicity of methylamino group compared with aromatic amino group in compound
2 and different reactivity of the electrophilic centers in 1 and 4 contribute equally to
1
the observed regioselectivity, resulting in 1,3,5-triazocines 6. The analysis of H and
13C NMR spectra of compounds 6 as well as single-crystal x-ray study of compound
6a (Fig. 1) leave no doubt about their correct structural assignment.
To sum up, hitherto unknown 1,3,5-benzotriazocines were synthesized on a
preparative scale through the regioselective cyclocondensation of easily accessible
tetrachloro-2-aza-1,3-dienes with 2-(aminomethyl)aniline. Further research of
Figure 1. Molecular structure of compound 6a was determined by single-crystal X-ray diffraction.

SYNTHESIS OF 1,3,5-BENZOTRIAZOCINES
717
cyclocondensations of chlorinated azadienes with bis-nucleophiles is presently in
progress in our laboratories.
EXPERIMENTAL
1H (500 MHz) and 13C (125 MHz) NMR spectra were recorded on Bruker
Avance DRX 500 spectrometer in dimethylsulfoxide (DMSO-d6) solution with tetra-
methylsilane (TMS) as an internal standard. Melting points were measured with a
Buchi melting-point apparatus and are uncorrected. Elemental analysis was carried
¨
out by the Analytical Laboratory of Institute of Bioorganic Chemistry and Petro-
chemistry, National Academy of Sciences of Ukraine. The chromatomass spectra
were recorded on an Agilent 1100 Series high-performance liquid chromatograph
equipped with a diode matrix with an Agilent LCnMSD SL mass selective detector,
allowing fast switching of the ionization modes. The chromatomass spectral analysis
parameters are as follows: column Zorbax SBC18 1.8 mm, 4.6.15 mm (PN 821975-
932); solvents: A, acetonitrile–water mixture (95:5), 0.1% trifluoroacetic acid, B,
0.1% aqueous trifluoroacetic acid; eluent flow 3 ml minꢀ1, injection volume 1 ml, UV
detectors 215, 254, 285 nm; the ionization method is atmospheric-pressure chemical
ionization (APCI), scanning range m=z 80–1000. The reaction progress was moni-
tored by thin-layer chromatography (TLC) on silica gel 60 F254 Merck.
Preparation and characterization details of compounds 1a–c[2] are available
from the literature; 2-(aminomethyl)aniline 2 was obtained from commercially
available source (Aldrich) and used without further purification.
X-Ray Structure Determination for 6a
Crystal data: C16H13Cl2N3, M 318.19, monoclinic, space group P21=c,
3
ꢁ
˚
˚
a ¼ 11.3880(5), b ¼ 10.8069(5), c ¼ 12.5643(6) A, a ¼ 94.161(3) , V ¼ 1542.20(12)A ,
Z ¼ 4, dc ¼ 1.370 g ꢂ cmꢀ3, m ¼ 0.417 mmꢀ1, F(000) ¼ 656, crystal size ca. 0.08 ꢃ 0.12 ꢃ
0.46 mm. All crystallographic measurements were performed at room temperature
on a Bruker Smart Apex II diffractometer operating in the x and / scan mode.
The intensity data were collected within the range of 1.79 ꢄ h ꢄ 28.32ꢁ using Mo-Ka
˚
radiation (k ¼ 0.71078 A). The intensities of 13575 reflections were collected (3825
unique reflections, Rmerg ¼ 0.039). The multiscan absorption correction (the mini-
mum and maximum apparent transmissions are 0.8314 and 0.9674) was applied.
The structure was solved by direct methods and refined by the full-matrix least-
squares technique in the anisotropic approximation for nonhydrogen atoms using
the Bruker SHELXTL program package.[9] Both chlorine atoms in the CHCl2 group
are disordered over two position with equal occupancies. All hydrogen atoms were
refined isotropically. In the refinement 3825 reflections (2265 reflections with
I ꢅ 2r(I)) were used. Convergence was obtained at R1 ¼ 0.0889 and wR2 ¼ 0.1282
for all reflections, and R1 ¼ 0.0446 and wR2 ¼ 0.1038, GOF ¼ 0.996 for observed
(262 parameters; observed=variable ratio 8.6, The largest and minimal peaks in
3
˚
the final difference map 0.18 and ꢀ0.26 e=A . Weighting scheme is as follows:
x ¼ 1=[r2(Fo2) þ (0.0495P)2 þ 0.4183P], where P ¼ (Fo2 þ 2Fc2)=3), Full crystallo-
graphic details have been deposited at Cambridge Crystallographic Data Centre

718
R. Y. VASYLYSHYN ET AL.
(CCDC). Any request to the CCDC for these materials should quote the full litera-
ture citation and reference number CCDC 900508.
The eight-membered cycle is nonplanar. Atoms N2N3C7C8 lie in the plane
˚
with mean deviation from plane 0.0061 A; atoms N1C1C2C9 situated inꢁplane with
˚
mean deviation of 0.027 A; dihedral angle between named planes is 82.2 .
˚
Bond distances N1–C7 and N2–C8 have normal lengths (1.282 and 1.290 A
=
respectively) that are typical for standard C N double bonds.
˚
Bond distances N2–C7 1.360(2) and N3–C8 1.331(2) A are short compared to
=
standard single C-N bond because of conjugation in between p-systems of two C N
double bonds or p-system of the double bond with a lone pair of N3 atoms.
In the crystal, molecules are connected in chains by weak hydrogen
N3-H3n . . . N1a bonds directed aꢁlong crystallographic axes 0z. The parameters of
˚
H-bond is N3–H3n–N1a 173.98 , N3–H3n 0.81, N3 . . . N1a 3.054 A. (By letter
‘‘a’’ the marked atom is connected to base atoms with symmetry operations x,
ꢀy þ 3 = 2, z ꢀ 1 = 2).
General Procedure for the Preparation of 4-Aryl-2-dichloromethyl-
5,6-dihydro-1,3,5-benzotriazocines (6a–c)
Compound 1 (3.5 mmol) and triethylamine (3.92 mL, 28 mmol) were added to a
solution of 2-(aminomethyl)aniline (0.43 g, 3.5 mmol) in dry THF (20 mL). The reac-
tion mixture was stirred at room temperature for 48 h and then the precipitated
triethylammonium hydrochloride was filtered off, and the solvent was removed
under reduced pressure. The crude product was washed with deionized water and
recrystallized from 2-propanol.
2-Dichloromethyl-4-phenyl-5,6-dihydro-1,3,5-benzotriazocin (6a). Com-
pound 6a was prepared following the general procedure from 1a (0.94 g). Yield 0.95 g
1
(85%), yellow crystals, mp 185–186 ꢁC (destr.). H NMR (500 MHz, DMSO-d6):
d ¼ 4.05 (dd, 1H, CH2), 4.69 (d, 1H, CH2), 7.00 (s, 1H, CHCl2), 7.04–7.81 (m, 9H,
3
ArH), 8.49 (d, JHH ¼ 0.5 Hz, 1H, NH). 13C NMR (125 MHz, DMSO-d6):
d ¼ 44.21, 74.26, 123.56, 124.75, 127.98, 128.51, 128.77, 129.42, 130.63, 131.87,
135.06, 149.23, 157.66, 160.96. Anal. calcd. for C16H13Cl2N3: C, 60.39; H, 4.12;
Cl, 22.28; N, 13.21. Found: C, 59.95; H, 4.24; Cl, 22.38; N, 13.17. LCnMS found
m=z 318 [M]þ.
2-Dichloromethyl-4-(4-methylphenyl)-5,6-dihydro-1,3,5-benzotriazocin
(6b). Compound 6b was prepared following the general procedure from 1b (1 g).
1
Yield 0.91 g (89%), yellow crystals, mp 174–175 ꢁC (destr.). H NMR (500 MHz,
DMSO-d6): d ¼ 2.33 (s, 3H, CH3), 4.16 (dd, 1H, CH2), 4.67 (dd, 1H, CH2), 6.98
(s, 1H, CHCl2), 7.01–7.70 (m 9H, ArH), 8.40 (s, 1H, NH). 13C NMR (125 MHz,
DMSO-d6): d ¼ 21.39, 44.18, 74.31, 123.57, 124.66, 127.94, 128.62, 129.26, 129.36,
130.59, 132.28, 141.80, 149.28, 157.53, 160.96. Anal. calcd. for C17H15Cl2N3: C,
61.46; H, 4.55; Cl, 21.34; N, 12.65. Found: C, 61.95; H, 4.38; Cl, 21.80; N, 12.07.
LCnMS found m=z 334 [M þ 2]þ.
3-(4-Chlorophenyl)-2-dichloromethyl-5,6-dihydro-1,3,5-benzotriazocin
(6c). Compound 6c was prepared following the general procedure from 1c (1.06 g).

SYNTHESIS OF 1,3,5-BENZOTRIAZOCINES
719
Yield 1.18 g (96%), yellow crystals, mp 177–178 ꢁC (destr.). Anal. calcd. for
C16H12Cl3N3: C, 54.50; H, 3.43; Cl, 30.16; N, 11.92. Found: C, 54.91; H, 3.28; Cl,
30.27; N, 11.67. 1H NMR (500 MHz, DMSO-d6): d ¼ 4.05 (dd, 1H, CH2), 4.68
(dd, 1H, CH2), 7.00 (s, 1H, CHCl2), 7.03–7.82 (m, 8H, ArH), 8.57 (s, 1H, NH).
13C NMR (125 MHz, DMSO-d6): d ¼ 44.20, 74.15, 123.56, 124.82, 128.27, 128.88,
129.46, 129.81, 130.65, 133.88, 136.71, 149.12, 156.64, 160.71. LCnMS found m=z
354 [M þ 1]þ.
SUPPORTING INFORMATION
1
Full experimental detail, H and 13C NMR spectra, and HPLC traces can be
found via the Supplementary Content section of this article’s Web page.
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