Abstract. 2-Methoxy-5-(3-methylfuroxan-4-yl)phenylhydrazine (Hy1) and 4,5-
methylendioxy-2-(3-methylfuroxan-4-yl)phenylhidrazine (Hy2) were introduced in the
reaction with paraformaldehyde in the presence of acetic acid as catalyst to afford two
new polyaza-heterocyclic compounds: 2,5-bis[2-methoxy-5-(3-methylfuroxan-4-yl)
phenylamino]-1,2,4,5-tetraazabicyclo[2.2.1]heptane (1) and 1,4-bis[4,5-(methylendioxy)-
2-(3-methylfuroxan-4-yl)phenylamino]-1,4-diazacyclohexa-2,5-diene (2), respectively.
The structure of 1 and 2 was determined by IR, HR MS, 1H NMR, 13C NMR, HSQC and
HMBC spectroscopy. Some interesting features in their NMR spectra and their formation
were explained.
8 trang |
Chia sẻ: thanhle95 | Lượt xem: 246 | Lượt tải: 0
Bạn đang xem nội dung tài liệu Structure of polyaza-heterocycles obtained from reaction of two (3-methylfuroxan-4-yl)phenylhydrazines with formaldehyde, để tải tài liệu về máy bạn click vào nút DOWNLOAD ở trên
JOURNAL OF SCIENCE OF HNUE DOI: 10.18173/2354-1059.2016-0049
Natural Sci. 2016, Vol. 61, No. 9, pp. 3-10
This paper is available online at
3
STRUCTURE OF POLYAZA-HETEROCYCLES OBTAINED FROM REACTION
OF TWO (3-METHYLFUROXAN-4-YL)PHENYLHYDRAZINES
WITH FORMALDEHYDE
Nguyen Huu Dinh
1
, Hoang Thi Tuyet Lan
2
and Trinh Thi Huan
3
1
Faculty of Chemistry, Hanoi National University of Education
2
Faculty of Chemistry, University of Transportation, Hanoi
3
Faculty of Chemistry, Hong Duc University, Thanh Hoa
Abstract. 2-Methoxy-5-(3-methylfuroxan-4-yl)phenylhydrazine (Hy1) and 4,5-
methylendioxy-2-(3-methylfuroxan-4-yl)phenylhidrazine (Hy2) were introduced in the
reaction with paraformaldehyde in the presence of acetic acid as catalyst to afford two
new polyaza-heterocyclic compounds: 2,5-bis[2-methoxy-5-(3-methylfuroxan-4-yl)
phenylamino]-1,2,4,5-tetraazabicyclo[2.2.1]heptane (1) and 1,4-bis[4,5-(methylendioxy)-
2-(3-methylfuroxan-4-yl)phenylamino]-1,4-diazacyclohexa-2,5-diene (2), respectively.
The structure of 1 and 2 was determined by IR, HR MS,
1
H NMR,
13
C NMR, HSQC and
HMBC spectroscopy. Some interesting features in their NMR spectra and their formation
were explained.
Keywords: Phenylhydrazine, formaldehyde, furoxan, eugenol, anethole.
1. Introduction
Furoxan derivatives were extensively studied as bioactive compounds. They possess
remarkable biological activities, such as anti-microbial and anti-parasitic properties,
mutagenic, immune-suppressive and anti-cancer effects, anti-aggregating and vasorelaxant
activity [1]. Several classes of hybrid compounds obtained combining appropriate
pharmacophoric groups with NO-releasing furoxan moiety (NO-donor) have been described [2].
A number of these such as NO-imidazole, NO-benzimidazole, NO-aspirin [3], NO-steroids [4],
and NO-ursodeoxycholic acid [5], are now under clinical study.
During recent years, some new arylhydrazines incorporating furoxan moiety (for
example in Figure 1) have been prepared in our laboratory as the key compounds for
synthesis of some series of hydrazones, 1,3-thiazolidin-4-ones and indoles. The reaction of
Hy1, Hy2 and other substituted phenylhydrazines with various aldehydes or ketones, as
general rule, gave aldohydrazones or ketohydrazones [6-8], while the reaction of Hy1, Hy2 with
formaldehyde afforded polyaza-heterocycles. Herein, their structure was established by
spectroscopic methods.
Received February 17, 2016. Accepted July 29, 2016.
Contact Nguyen Huu Dinh, e-mail address: huudinhhnue@gmail.com
Nguyen Huu Dinh,
Hoang Thi Tuyet Lan and Trinh Thi Huan
4
Figure 1. Two new arylhydrazines incorporating furoxan moiety
(The numeration on the structures is used specifically for NMR analysis only)
2. Content
2.1. Experiment
Synthesis of 2-methoxy-5-(3-methylfuroxan-4-yl)phenylhydrazine (Hy1) and 4,5-
methylendioxy-2-(3-methylfuroxan-4-yl)phenylhyrazine (Hy2): Compound Hy1, Hy2 (Figure 1)
were synthesized according to our manner, Hy1 - from anethole (the main component of
Star Anise oil) by four consecutive reaction steps [9], Hy2 - from safrole (the main
component of Sassafras oil) by five consecutive reaction steps [10].
Reaction of Hy1 and Hy2 with formaldehyde: A solution of Hy1 (or Hy2) (1 mmol),
paraformaldehyde (150 mg) and acetic acid (1 drop) in dry ethanol (30 - 50 mL) was
refluxed over 5 - 6 hours. The reaction mixture was allowed to stand at room temperature.
The resulting precipitate was collected and recrystallized to obtain products 1 and 2
respectively (see Table 1).
Table 1. Some details of the products 1 and 2
Arylhydrazine
Solvent for
recrystallization
Form Mp,
o
C
Yield,
%
1 Hy1 EtOH/Dioxane 2:1
Light yellow
needles
215 - 216 72
2 Hy2 EtOH/CHCl3 1:2
Light yellow
needles
230 - 232 65
Study of structure: IR spectra were recorded on an IMPACK-410 NICOLET
spectrometer in KBr discs at 400 - 4000 cm
-1
. HR mass spectra were recorded using
AutoSpec-Waters spectrometer. NMR spectra were recorded on a Bruker AVANCE 500
MHz spectrometer, in d6-DMSO with TMS as internal standard, at 298 - 300 K.
2.2. Results and discussion
The reaction of phenylhydrazine with aldehydes and ketones was developed by Fischer [11].
The products of this reaction are usually hydrazones. However, when formaldehyde is
reacted with phenylhydrazine, some products can be isolated [12]. None of these products is
Structure of polyaza-heterocycles obtained from reaction of two (3-methylfuroxan-4-yl)
5
the formaldehyde phenylhydrazone (PhNHN=CH2). One source [13] reports the formaldehyde
phenylhydrazone as a liquid. However, no characterization of this liquid can be found in the
literature. For determining formaldehyde in environment, reaction of phenylhydrazine with
formaldehyde is used [14, 15], however,the structure of product of this reaction was not
described. In view of the above-mentioned findings, in order to ascertain the structure of
obtained products 1 and 2, their IR, MS,
1
H NMR,
13
C NMR, HSQC and HMBC spectra
were used. For compound 1, the spectroscopic data and derived structure information are
listed in Table 2; its HMBC spectrum is presented in Figure 2.
Table 2. Spectroscopic data and derived structure information for 1
Spectroscopy Spectroscopic data Obtained structure information
IR, (cm
-1
)
-; 3041, 3000; 2942, 2836; 1603,
1595, 1521
Absent NH; Present: aromatic CH;
saturated CH; aromatic ring.
EI MS, (au)
M = 508.1831 Associated with C23H24N8O6 =
508.1819, molecule containing two
residues of Hz1 ~ 234.
1
H NMR,
δ (ppm),
J (Hz), see
the right part
of Figure 2.
7.81 d,
4
J 2.0, 1H; 7.31 dd,
3
J 8.5,
4
J 2.0, 1H; 7.16 d,
3
J 8.5, 1H.
Aromatic H6; H4; H3, respectively.
4.47 d,
2
J 8, 1H; 3.78 d,
2
J 8, 1H;
Proof effect.
3.72 s, 1H.
Two non-equivalent protons in N-
CH2-N group.
One of two equivalent protons in N-
CH2-N group.
3,86 s, 3H and 2.30 s, 3H. Three protons H7 and three protons
H10.
13
C NMR,
δ (ppm), see
Figure 2.
12 carbon signals: 157.20, 150.90,
140.65, 121.39, 118.66, 114.46,
112.86, 112.21, 81.34, 72.40,
55.85, 9.07.
8 none-quivalent sp
2
-carbon atoms
(named C1-C6, C8, and C9) and 4
non-equivalent sp
3
-carbon atoms
(named C7, C10-C12).
HSQC,
δ (ppm),
The signals at 114.46, 121.39 and
112.21 have cross peaks with H6,
H4 and H3, respectively.
Signal at 114.46 belongs to C6;
121.39 to C4, and 112.21 to C3.
The signal at 81.34 has cross
peaks with both doublets at 4.47
and 3.78.
Two non-equivalent protons (named
H11a and H11b) attach to one carbon
atom (named C11).
The signal at 72.74 has cross peak
with singlet of 2 protons at 3.72.
The signals at 55.85 and 9.07
have cross peaks with 3 protons
H7 and 3 protons H10.
Two equivalent protons in N-CH2-N
group (named H12); signal at 72.74
belongs to C12. Signal at 55.85
belongs to C7; 9.07 - C10.
Nguyen Huu Dinh,
Hoang Thi Tuyet Lan and Trinh Thi Huan
6
HMBC,
δ (ppm), see
Figure 2.
The cross peaks of H3, H4
and H6 allowed assigns the
signals of C1-C6 and C8.
Signal at 140.65 belongs to C1,
150.90 - C2, 112.21 - C3, 121.39 - C4,
118.66 - C5, 114.46 - C6, 157.20 - C8.
C1 have cross peaks with
both H11a (peak a) and H11b
(peak c).
Group methylen C(H11a) (H11b)
attaches to N.
C11 have cross peak with
H12 (peak d). C12 have cross
peak with H11a (peak b).
Group methylen C(H12)2 attaches
to N.
Cross peaks e and f show the
signals of C8 and C9,
respectively.
Signal at 157.20 belongs to C8,
signal at 112.86 – C2.
Figure 2. HMBC spectrum of compound 1
For compound 2, the spectroscopic data and obtained structure information are listed in
Table 3, its HMBC spectrum is presented in Figure 3.
Structure of polyaza-heterocycles obtained from reaction of two (3-methylfuroxan-4-yl)
7
Table 3. Spectro-scopic data and derived structure information for 2
Spectroscopy Spectroscopic data Obtained structure information
IR, (cm
-1
) 3295; 3096, 3000; 2980, 2903;
1635; 1593, 1502.
Present: NH; aromatic CH; alkene
CH; aromatic ring: Absent:
saturated CH
EI MS, (au) M = 548.1416 Associated with C24H20N8O8 =
548.1404, molecule containing two
residues of Hz2 ~ 496.
1
H NMR,
δ(ppm), J(Hz),
see the right part
of Figure 3.
9.70 s, 1H; 6.98 s, 1H; 6.91 s,
1H;
Present: NH; two para phenyl
protons (H3, H6).
6.88 d,
3
J 12, 1H; 6.23 d,
3
J 12,
1H; Proof effect.
Two alkene protons in cis-
configuration.
6.03 s, 2H and 1.99 s, 3H. Two protons H7 and three protons
H10.
13
C NMR,
δ (ppm),
see Figure 3.
11 carbon signals: 156.37,
150.53, 140.58, 140.18, 129.64,
114.03, 109.21, 101.45, 100.86,
95.47, 8.24.
9 non-equivalent sp
2
-carbon atoms
(named C1-C6; C8, C9, C11), 2
nonequivalent sp
3
-carbon atoms
(named C7, C10).
HSQC,
δ (ppm),
The signals at 109.21 and 95.47
have cross peaks with H3 and
H6, respectively.
Signal at 109.21 belongs to C3, and
95.47 to C6.
The signal at 129.64 has cross
peaks with both doublets at 6.88
and 6.23.
Two non-equivalent protons attach
to 2 equivalent sp
2
-carbon atoms
(named C11/C12).
The signal at 101.45 has cross
peak with 2 protons H7. The
carbon signal at 8.24 has cross
peaks with 3 protons H10.
Signal at 101.45 belongs to C7; and
8.24 to C10.
HMBC,
δ (ppm),
see Figure 3.
The pairs of signals m-m’, n-n’,
p-p’, v-v’, w-w’ and z-z’
associate with H11, H3, H6,
H12, H7 and H10, respectively.
These pairs of signals confirm the
assignment of C11, C3, C6, C12,
C7 and C10, respectively, according
to the HSQC spectrum.
Nguyen Huu Dinh,
Hoang Thi Tuyet Lan and Trinh Thi Huan
8
The cross peak q of H3 and x of
H10 show the signal of C8; y of
H10 - C9. The cross peaks k, l, o
of H6; r, s of H3; t, u of H7
allow to assign the signals of
C5, C4, C1 and C2.
Signal at 156.37 belongs to C8,
114.03 – C9, 150.53 – C5, 140.58 –
C4, 140.18 – C1, and 100.86 – C2.
Proton NH has cross peaks: g
with C1, i with C2, j with C6
and h with C11/C12.
This proton attaches to N, while
C11/12 attaches to N.
Figure 3. HMBC spectrum of compound 2
The structure information in Table 2 and 3 allowed describing structure of 1 and 2 as in
Figure 4. For 1, four N atoms and two C atoms (C11, C11’) make a six-member ring in boat
form, two residues of Hz1/ two protons H12/C11 and C11’ are equivalent, but H11a and
H11b as well as H11’a and H11’b are non-equivalent (they give rise to two doublets with
proof effect and J = 8 Hz).
For 2, two N atoms and 4 carbon atoms (C11, C11’, C12, C12’) make a flat six-
member ring, two residues of Hz2 are equivalent. It is interesting that four carbon atoms
C11, C11’, C12, C12’ are equivalent, while H11 and H12 as well as H11’ and H12’ are non-
equivalent (they give rise to two doublets with proof effect and J = 12 Hz). It is possible that
Structure of polyaza-heterocycles obtained from reaction of two (3-methylfuroxan-4-yl)
9
intramolecular hydrogen bonding make two residues of Hy2 (N-C10) become rigid and
more bulky groups, thus they cannot freely rotate about the N-N bond. In the
consequence, H11 as well as H11’ fall into the deshielding region of the benzene ring
whereas H12 as well as H12’ do not.
Figure 4. Structure of compounds 1 and 2
The formation of 1 and 2 can be explained as shown in reaction schemes (Figure 5) in
which Ar
1
-NHNH2 is Hy1, Ar
2
-NHNH2 is Hy2. For Hy1 (see Figure 1) formaldehyde can
attach to both N and N to form stable five-membered and six-membered rings. For Hy2
(see Figure 1), since the furoxan group sterically hinders the reaction in N, formaldehyde
can only attach to N alone. Thus, the stable six-membered ring was formed by the
dimerization involved the hydride shift as shown in Figure 5.
Figure 5. The reaction pathway for formation of compounds 1 and 2
3. Conclusion
Two new arylhydrazines incorporating furoxan moiety (Hy1 and Hy2) were introduced
in the reaction with paraformaldehyde in the presence of acetic acid as catalyst. It is shown
that, for Hy1, formaldehyde can attach to both N and N to form 2,5-bis[2-methoxy-5-(3-
methylfuroxan-4-yl)phenylamino]-1,2,4,5-tetraazabicyclo[2.2.1]heptane (1) while for Hy2
formaldehyde can only attach to N alone to form 1,4-bis[4,5-(methylendioxy)-2-(3-
methylfuroxan-4-yl)phenylamino]-1,4-diazacyclohexa-2,5-diene (2). The structure of 1 and 2
was determined by IR, MS,
1
H NMR,
13
C NMR HSQC, HMBC spectroscopy. Some
interesting features in their NMR spectra and in their formation were explained.
Nguyen Huu Dinh,
Hoang Thi Tuyet Lan and Trinh Thi Huan
10
REFERENCES
[1] H. Cerecetto and W. Porcal, Mini Rev. Med. Chem., 2005, 5 , 57.
[2] P. G. Wang, M. Xian, X. Tang, X. Wu, Z. Wan, T. Cai, A. J. Janczuk, Chem. Rev.,
2002, 102, 1091-1134.
[3] S. Freduzzi, G. Mariucci, M. Tantucci, P. del Soldato, M. V. Ambrosini, Neurosci.
Lett., 2001, 302, 121-24.
[4] Tallet D., del Soldato P., Oudart N., Burgaud J. L. Bio-chem. Biophys. Res.
Commun., 2002, 290, 125-30.
[5] Fiorucci S., Antonelli E., Morelli, O., Mencarelli, A., Casini A., Mello T.,
Palazzetti B., Tallet D., del Soldato P., Morelli A. Proc. Natl. Acad. Sci. U.S.A.,
2001, 98, 8897-8902.
[6] N. H. Dinh, N. Q. Trung, N. D. Dat, N. Hien. Journal of Heterocyclic Chemistry.
2012, 49 (5), 1077-1085.
[7] N. H. Dinh, T. T. Huan, H. T. T. Lan, Sang-Bae Han, Heterocycles, 2013, 87, 2319-2332.
[8] T. V. Hung, N. Q. Dat, L. N. Van, L. T. Tap. Journal of Pharmacy, 2000, 8, 15-17.
[9] N. H. Dinh, N. T. Ly, T. T. Huan. Vietnam Journal of Chemistry, 2005, 43, 128-132
[10] N. H. Dinh, N. Q. Trung, N. T. Linh. Vietnam Journal of Chemistry. 2009, 47 (4A),
pp. 763-767.
[11] E. Fischer. Chemische Berichte. 1875, 8, 589.
[12] Von E. Schmitz and R. Ohme. Justus Liebig's Annalen der Chemie. 1960, 635, 82.
[13] R. L. Shriner,.R. E. Puson and D. Y. Curtin. The Systematic Identification of Organic
Compounds. 4th ed. John Wiley and Sons, Inc., New York, N.Y. 1956.
[14] KP Shivastaw, S. Singh. Biologicals. 1995, 23 (1), 47-53.
[15] Abeer S. El- Maghraby and Abd El- Hakim M. Ali. Global Veterinaria. 2015, 14
(4), 546-552.