C-phosphorylated furazano-[3,4-b]piperazines

Article abstract of DOI:10.1007/s10593-006-0204-1

The reaction of phosphorylated α-chloroacetaldehydes with 3,4-diaminofurazane gives enamines, bisenamines, semiaminals, and O,N-acetals, whose cyclization leads to previously unreported phosphorylated furazano[3,4-b]piperazines.

Full text of DOI:10.1007/s10593-006-0204-1

Chemistry of Heterocyclic Compounds, Vol. 42, No. 8, 2006
C-PHOSPHORYLATED FURAZANO-
[3,4-b]PIPERAZINES
Kh. A. Asadov, F. I. Guseinov, B. P. Strunin, D. V. Beskrovny, and I. A. Litvinov
The reaction of phosphorylated α-chloroacetaldehydes with 3,4-diaminofurazane gives enamines,
bisenamines, semiaminals, and O,N-acetals, whose cyclization leads to previously unreported
phosphorylated furazano[3,4-b]piperazines.
Keywords: O,N-acetal, bisenamines, 3,4-diaminofurazane, enamines, semiaminal, phosphorylated
α-chloroacetaldehydes, furazano[3,4-b]piperazines.
Derivatives of furazano[3,4-b]piperazines are used as energy-rich materials, intermediates in organic
synthesis, and biologically active compounds. However, preparative methods for obtaining these compounds and
the chemical properties of these derivatives, which may have potential as biologically active compounds, have
not been studied adequately [1, 2].
With the aim of synthesizing C-phosphorylated furazanopiperazines, we studied the reactions of
α-chloroacetaldehydes 1 with diaminofurazane. The condensation of phosphorylmonochloroacetaldehydes 1a,b
with 3,4-diaminofurazane proceeds in ethanol at reflux and leads to the formation of monoenamine 2 and
bisenamine 3 depending on the ratio of the starting reagents.
NH2
N
P(O)(OR)2
O
N
N
H
Cl
Cl
H2N
H2N
2a,b
N
N
H
Cl
(RO)2P
O
O
+
H
O
N
P(O)(OR)2
P(O)(OR)2
N
1a,b
O
N
N
H
Cl
3a,b
2, 3 a R = Et, b R = i-Pr
Enamines 2 and 3 are white crystalline compounds. The IR band for their amino group is found at
3350 cm-1 and is superimposed on the stretching band of the secondary amino group to give a complex overall
shape. The low value for νNH2 in KBr pellets indicates hydrogen bonding of this group.
__________________________________________________________________________________________
Kazan State Technological University, 420015 Kazan, Russia; e-mail: eltos@kai.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1220-1229, August, 2006. Original article submitted
December 2, 2003; revision submitted April 6, 2006.
0009-3122/06/4208-1059©2006 Springer Science+Business Media, Inc.
1059

1
The protons of the NH–CH=CCl fragment in the H NMR spectra of 2 and 3 in DMSO-d6 and
acetone-d6 are seen as a characteristic group of signals: a doublet at 7.7-7.8 ppm (CH=) with 3JPH = 12.5 Hz and
downfield doublet at 8.9-9.0 ppm (NH).
1
The methine group proton in the H NMR spectrum of 3 is not shifted downfield and the broad signal
corresponding to NH2 group protons is not seen.
As assumed, at higher temperature in xylene at reflux, 2b undergoes heterocyclization as the result of
intramolecular nucleophilic substitution to give hydrochloride 4.
H
N
N
N
∆
.
HCl
O
2b
(i-PrO)
2 P
N
H
O
4
1
The H NMR spectrum of 4 in DMSO-d6 shows a doublet of doublets for the =CH group proton at
7.75 ppm as well as two doublets at 8.10 (+NH2) and 9.00 ppm (NH) with 2:1 intensity ratio. The singlet
characteristic for NH2 group protons at 6.2 ppm (for 2b) completely disappears. The signal in the 31P NMR
spectrum is shifted from 9.89 to 11.00 ppm.
The IR spectrum of 4 has stretching bands for the phosphoryl group at 1280 cm-1, C=C bond at
1635 cm-1, secondary amino group at 3100 cm-1, and +NH2 group at 3280 cm-1.
In previous work [3], we showed that diethoxyphosphorylphenyl-α-chloroacetaldehyde in a polar
solvent (acetonitrile) reacts with diaminofurazane to give semiaminal 5a but this reaction in ethanol gives
O,N-acetal 5b, whose structure was demonstrated by X-ray diffraction structural analysis.
O
O
(EtO)2P
Ph
Cl
H
H2N
H2N
N
(EtO)2P
N
N
N
N
Cl
MeCN or EtOH
O
O
+
OR
H2N
Ph
CHO
5a,b
a R=H, b R=Et
Since the crystal of 5b is centrosymmetric, this compound exists as a racemate (Fig. 1).
The conformation along the P–C(12) and C(8)–C(12) bonds is staggered, perhaps due to steric effects; steric
hindrance is minimal in this conformation. The P=O and C–Cl bonds in 5b are in gauche arrangement, while the
C(8)–C(12) bond is trans to the phosphoryl bond. The phenyl substituent at C(12) is in an eclipsed conformation
with the C(12)–Cl bond, probably due to steric hindrance arising from the bulky substituents at C(12). The
aminofurazane substituent has planar conformation. The N(2)–C(3)–N(7)–C(8) torsion angle is 11.5(4)°, resulting
from conjugation of the unshared electron pair of N(7) with the π-system of the furazane ring. The C(3)–N(7) bond
length (1.345(4) Å) corresponds to this conjugation.
The bond lengths and valence angles in the phosphonate fragment, benzene ring, and furazane ring are
ordinary.
The crystal of 5b is stabilized by N–H···O and N–H···N hydrogen bonding (Fig. 2) between the
aminofurazane group and phosphoryl group oxygen atom N(7)–H···O(21') (3/2-x, 1/2+y, 1/2-z), N(7)–H 0.93,
N(7)···O(21') 3.042(3); H···O(21') 2.15 Å, angle N(7)–H···O(21') 161° and also between the amino NH2 group,
phosphoryl group, and one of the nitrogen atoms of the furazane ring: N(6)–H(61)···O(21'), N(6)–H(61) 0.75,
1060

N(6)···O(21') 2.903(4), H(61)···O(21') 2.16 Å, angle N(6)–H(61)···O(21') 173°; N(6)–H(62)···N(5'') (2-x, 2-y, -z), N(6)–H(62)
1.12, N(6)···N(5'') 3.019(4), H(62)···N(5'') 1.94 Å, angle N(6)–H(62)···N(5'') 161°.
A two-dimensional molecular layer is formed in the X0Z plane (perpendicular to the 0Y axis) due to
these hydrogen bonds.
The parallel packing of these layers in the crystal leads to the formation of molecular stacks.
Fig. 3 shows that the arrangement of the benzene and furazane rings in these stacks suggests a stacking
effect. However, the geometrical parameters do not correspond to those formally adopted for π–π interactions.
TABLE 1. Characteristics of the Products Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
85
Cl
N
P
2а
C8H14ClN4O4P
11.88
11.97
18.81
18.89
10.49
10.45
130-132
2b
3а
3b
4
C10H18ClN4O4P
C14H24Cl2N4O7P2
C18H32Cl2N4O7P2
C10H18ClN4O4P
C14H20ClN4O5P
C16H24ClN4O5P
C16H23N4O5P
10.91
10.94
14.36
14.40
12.87
12.93
10.88
10.94
9.18
9.09
8.57
8.48
17.22
17.26
11.28
11.36
10.17
10.20
17.16
17.26
14.27
14.34
13.44
13.38
14.34
14.66
14.42
14.34
9.44
9.55
12.53
12.58
11.23
11.29
9.48
9.55
7.98
7.94
7.55
7.41
8.22
8.12
8.01
7.94
155-158
145-146
168-170
220-221
152-153
158-159
150-151
166-167
87
78
81
83
83
80
76
69
5а
5b
6
—
7
C14H20ClN4O4P
9.24
9.09
Fig. 1. Geometry of 5b in the crystal.
1061

TABLE 2. IR, 1H and 31P NMR Spectra of Products Synthesized
31Р NMR
spectrum,
δ, ppm
Com-
pound
IR spectrum, ν, cm-1
1Н NMR spectrum, δ, ppm. (J, Hz)*
2а
1280 (Р=О), 1610
(С=С), 3100 (NH),
3350 (NH2)
1.25 (6Н, t, 3JHH = 12.5, 2СН3); 4.00 (4Н, m,
2ОСН2); 6.00 (2Н, br. s, NH2); 7.70 (1H, dd,
3JHH = 8.75, 3JPH = 12.5, =СН); 8.90 (1Н, d,
3JHH = 12.5, NH)
9.8
2b
—
1.25 (12Н, dd, 3JHH = 7.5, 4СН3); 4.60 (2Н, m,
2ОСН); 6.20 (2Н, br. s, NH2); 7.75 (1H, dd,
3JHH = 7.5, 3JPH = 12.5, =СН); 9.00 (1Н, d,
3JHH = 10.0, NH)
9.89
3а
3b
4
1280 (Р=О), 1605
(С=С), 3140 (NH)
1.20 (12Н, dt, 3JHH = 12.5, 4СН3); 4.00 (8Н, m,
4ОСН2); 7.75 (2H, dd, 3JPH = 3JHH = 12.5, 2СН=);
8.90 (2Н, d, 3JHH = 12.5, 2NH)
1.25 (24Н, dt, , 3JHH = 15, 8СН3); 4.70 (4Н, m,
4ОСН); 7.80 (2H, dd, 3JPH = 12.5, 3JHH = 17.5,
2СН=); 9.00 (2Н, d, 3JHH = 10.0, 2NH)
12.3
12.5
11.0
—
1280 (Р=О), 1635
(С=С), 3100 (NH),
3280 (H2N+)
1.20 (12Н, dt, 3JHH = 17.5, 4СН3); 4.60 (2Н, m,
2ОСН); 7.75 (2H, dd, 3JHH = 7.5, 3JPH = 10.0,
СН=); 8.10 (2Н, d, 3JHH = 10.0, +NH2);
9.00 (1Н, d, NH)
5а
5b
6
1280 (Р=О),
1650 (СH–O),
3100 (NH),
1.10 (6Н, dt, 3JHH = 22.5, 2СН3); 3.90 (4Н, m,
15.0
2ОСН2); 5.50 (1H, d, 3JРH = 5, ОСН);
6.00 (2Н, br. s, NH2); 7.25 (3Н, m, C6H5);
3250 (NH2), 3340 (OH) 7.60 (2H, m, C6H5); 10.30 (1H, br. s, ОН);
11.50 (1Н, br. s, NH)
1280 (Р=О),
1640 (СH–O),
1.0 (9Н, dt, 3JHH = 20, 3СН3); 3.75 (4Н, m,
15.15,
15.20
2ОСН2); 4.00 (2Н, q, 3JHH = 12.5, ОСН2);
3100 (NH), 3250 (NH2) 5.75 (1H, d, 3JРH = 5, ОСН); 6.10 (2Н, br. s,
NH2); 7.30 (3Н, m, C6H5); 7.80 (2H, m, C6H5);
11.70 (1Н, br. s, NH)
1280 (Р=О),
1.15 (9Н, dt, 3JHH = 22.5, 3СН3); 3.80 (4Н, m,
20.83,
20.91
1620 (С–O), 3250 (NH) 2ОСН2); 4.10 (2Н, q, 3JHH = 10.0, ОСН2);
5.00 (1H, dt, 3JHH = 7.5, 3JPH = 10.0, ОСН);
5.50 (2Н, s, NH2); 7.35 (3Н, m, C6H5);
7.50 (2H, m, C6H5)
7
1287 (Р=О),
1.15 (6Н, dt, 3JHH = 20, 2СН3); 4.00 (4Н, m,
19.8
1570 (С–O), 3200 (NH) 2ОСН2); 5.30 (1H, dd, 3JHH = 7.5, 3JPH = 12.5,
ОСН); 7.25 (3Н, m, C6H5); 7.50 (2H, m, C6H5);
8.20 (2Н, d, 3JPH = 7.5, +NH2); 9.00 (1Н, d,
3JHH = 12.5, NH); 10.50 (1H, d, 3JHH = 10.0, ОН)
_______
* Solvents: (CD3)2SO for 2a, 4, 5a,b, 7 and (CD3)2CO for 2b, 3a,b, and 6.
In previous work [3], we reported that the reaction of ester 5b with sodium ethylate in ethanol gives a
high yield of a condensed heterocyclic compound, namely, 4-diethoxyphosphoryl-5-ethoxy-4-phenyl-3,4,5,6-
tetrahydrofurazano[3,4-b]piperazine (6), which is the first reported phosphorylated furazano[3,4-b]piperazine.
H
H
N
N
EtONa
EtO
O
5b
Ph
N
N
H
(EtO)2P
O
6
1062

TABLE 3. Lengths of Major Bonds (d) in 5b
Bond
d, Å
Bond
d, Å
1.801(3)
1.464(2)
1.561(2)
1.553(2)
1.842(3)
1.382(4)
1.399(4)
1.406(4)
1.437(5)
1.458(5)
1.458(5)
1.305(4)
1.299(4)
1.345(4)
1.345(4)
1.452(4)
1.435(4)
1.542(4)
1.409(9)
1.541(4)
1.386(5)
1.399(5)
1.420(5)
1.06(3)
Cl(2)−C(12)
P(20)−O(21)
P(20)−O(22)
P(20)−O(25)
P(20)−C(12)
O(1)−N(2)
O(1)−N(5)
O(9)−C(8)
O(9)−C(10)
O(22)−C(23)
O(25)−C(26)
N(2)−C(3)
N(5)−C(4)
N(6)−C(4)
N(7)−C(3)
N(7)−C(8)
C(3)−C(4)
C(8)−C(12)
C(10)−C(11)
C(12)−C(13)
C(13)−C(14)
C(13)−C(18)
C(14)−C(15)
C(14)−H(14)
C(15)−C(16)
C(16)−C(17)
C(17)−C(18)
C(23)−C(24)
1.346(6)
1.338(6)
1.375(5)
1.463(8)
In a continuation of a study of the reactivity of semiaminals 5 and in an attempt to obtain new condensed
C-phosphorylated heterocyclic furazane derivatives, we investigated the intramolecular heterocyclization of
O,N-acetal 5a under vigorous conditions. Heating 5a in toluene at reflux leads to an intramolecular nucleophilic
reaction and formation of furazano[3,4-b]piperazine hydrochloride 7.
Fig. 2. Hydrogen bonding system in the crystal of 5b.
1063

Fig. 3. Stacking of molecules in the crystal of 5b.
H
H
N
N
HO
∆
.
O
HCl
5a
Ph
N
N
H
(EtO)2P
O
7
Heterocycle 7 is a white crystalline compound with good solubility in ethanol, DMSO, and acetonitrile.
The reaction proceeds with involvement of the furazane NH2 group and α-halogen atom and is complete after
8 h at 105-110°C.
The IR spectrum of 7 shows a band at 1570 cm-1 due to stretching vibrations of the CH–O group as well
as bands at 1287 (P=O), 3200 (NH), 3250 (+NH2), and 3340 cm-1 (OH).
The phosphorus signal in the 31P NMR spectrum of this compound is shifted from 15.0 to 19.8 ppm,
indicating a heterocyclization reaction. The finding of two signals in the 31P NMR spectrum shows formation of
a mixture of diastereomers.
1
The signal for the semiaminal proton in the H NMR spectrum of 7 is shifted upfield from 5.50 to
5.30 ppm. The broad singlet for the NH2 group protons in the vicinity of 6.00 ppm in 5a disappears and a
+
doublet appears at 8.20 ppm, probably indicative of protons of the NH2 group. While the OH and NH group
proton signals in the starting semiaminal are seen as broad singlets at 10.30 and 11.50 ppm, respectively, these
signals for heterocycle 7 appear as a doublet at 10.50 and 9.00 ppm, respectively.
Thus, the products of the reaction of phosphorylated chloro aldehydes with diaminofurazane, namely,
enamines 2 and 3, semiacetal 5a, and O,N-acetal 5b are convenient starting compounds for the synthesis of
phosphorylated furazano[3,4-b]piperazines.
1064

TABLE 4. Bond Angles (ω) in 5b
Bond angle
ω, deg.
Bond angle
C(8)−C(12)−C(13)
ω, deg.
116.2(1)
114.2(1)
112.2(1)
104.2(1)
100.8(1)
108.0(1)
110.5(2)
114.6(3)
119.1(2)
124.6(2)
106.1(3)
105.3(3)
120.8(2)
124.1(3)
108.6(3)
127.3(3)
123.9(3)
111.4(2)
114.7(2)
109.5(2)
109.2(2)
123.3(3)
117.8(3)
118.9(3)
117.5(3)
122.3(4)
119.3(4)
121.7(4)
120.2(3)
109.5(3)
126.5(3)
112.4(2)
106.3(2)
113.7(2)
111.0(5)
103.1(1)
108.8(2)
110.0(4)
110.7(4)
O(21)−P(20)−O(22)
O(21)−P(20)−O(25)
O(21)−P(20)–C(12)
O(22)−P(20)−O(25)
O(22)−P(20)−C(12)
O(25)−P(20)−C(12)
N(2)−O(1)−N(5)
C(8)−O(9)−C(10)
P(20)−O(22)−C(23)
P(20)−O(25)−C(26)
O(1)−N(2)−C(3)
O(1)−N(5)−C(4)
C(3)−N(7)−C(8)
N(2)−C(3)−N(7)
N(2)−C(3)−C(4)
N(7)−C(3)−C(4)
N(5)−C(4)−N(6)
Cl(2)−C(12)−C(13)
P(20)−C(12)−C(8)
P(20)−C(12)−C(13)
C(12)−C(13)−C(14)
C(12)−C(13)−C(18)
C(14)−C(13)−C(18)
C(13)−C(14)−C(15)
C(14)−C(15)−C(16)
C(15)−C(16)−C(17)
C(16)−C(17)−C(18)
С(13)−С(18)−С(17)
N(5)−C(4)−C(3)
N(6)−C(4)−C(3)
O(9)−C(8)−N(7)
O(9)−C(8)−C(12)
N(7)−C(8)−C(12)
O(9)−C(10)−C(11)
Cl(2)−C(12)−P(20)
Cl(2)−C(12)−C(8)
O(22)−C(23)−C(24)
O(25)−C(26)−C(27)
TABLE 5. Torsion Angles (τ) in 5b
Torsion angle
τ, deg.
Torsion Angle
τ, deg.
-60.5(3)
66.1(3)
68.9(3)
-46.0(3)
-169.3(2)
-179.0(3)
0.4(3)
O(21)−P(20)−O(22)−C(23)
O(25)−P(20)−O(22)−C(23)
C(12)−P(20)−O(22)−C(23)
O(21)−P(20)−O(25)−C(26)
O(22)−P(20)−O(25)−C(26)
C(12)−P(20)−O(25)−C(26)
O(21)−P(20)−C(12)−Cl(2)
O(21)−P(20)−C(12)−C(8)
O(21)−P(20)−C(12)−C(13)
O(22)−P(20)−C(12)−Cl(2)
O(22)−P(20)−C(12)−C(8)
O(22)−P(20)−C(12)−C(13)
O(25)−P(20)−C(12)−Cl(2)
O(25)−P(20)−C(12)−C(8)
O(25)−P(20)−C(12)−C(13)
N(5)−O(1)−N(2)−C(3)
N(2)−O(1)−N(5)−C(4)
C(10)−O(9)−C(8)−N(7)
C(10)−O(9)−C(8)−C(12)
C(8)−O(9)−C(10)−C(11)
P(20)−O(22)−C(23)−C(24)
P(20)−O(25)−C(26)−C(27)
N(7)−C(3)−C(4)−N(5)
N(7)−C(8)−C(12)−Cl(2)
N(7)−C(8)−C(12)−P(20)
N(7)−C(8)−C(12)−C(13)
O(1)−N(2)−C(3)−N(7)
O(1)−N(2)−C(3)−C(4)
O(1)−N(5)−C(4)−N(6)
O(1)−N(5)−C(4)−C(3)
C(8)−N(7)−C(3)−N(2)
C(8)−N(7)−C(3)−C(4)
C(3)−N(7)−C(8)−O(9)
C(3)−N(7)−C(8)−C(12)
N(2)−C(3)−C(4)−N(5)
N(2)−C(3)−C(4)−N(6)
Cl(2)−C(12)−C(13)−C(14)
Cl(2)−C(12)−C(13)−C(18)
P(20)−C(12)−C(13)−C(14)
P(20)−C(12)−C(13)−C(18)
C(8)−C(12)−C(13)−C(14)
C(8)−C(12)−C(13)−C(18)
C(12)−C(13)−C(14)−C(15)
C(18)−C(13)−C(14)−C(15)
C(12)−C(13)−C(18)−C(17)
C(14)−C(13)−C(18)−C(17)
C(13)−C(14)−C(15)−C(16)
C(14)−C(15)−C(16)−C(17)
C(15)−C(16)−C(17)−C(18)
C(16)−C(17)−C(18)−C(13)
177.9(3)
-19.57(3)
-147.3(3)
106.1(3)
74.5(2)
177.9(3)
-1.5(4)
-167.3(2)
-44.2(2)
-161.2(1)
-43.1(2)
80.1(2)
11.5(4)
-167.8(3)
-116.6(3)
122.5(3)
0.7(4)
-52.3(2)
65.9(2)
-178.7(3)
-1.6(4)
-171.0(2)
-1.4(3)
178.7(2)
111.9(3)
-67.9(3)
-121.8(3)
58.5(3)
-179.2(3)
0.5(5)
1.8(3)
78.6(3)
-156.4(3)
93.4(5)
-103.0(4)
94.7(4)
179.8(3)
0.03(6)
-0.8(6)
-179.9(3)
0.7(5)
N(7)−C(3)−C(4)−N(6)
O(29)−C(8)−C(12)−Cl(2)
O(9)−C(8)−C(12)−P(20)
O(9)−C(8)−C(12)−C(13)
-55.3(3)
-170.2(2)
66.5(3)
0.5(6)
0.2(6)
-0.4(6)
1065

EXPERIMENTAL
The IR spectra were taken in vaseline mull or KBr pellets on a UR-20 spectrometer. The X-ray
diffraction structural analysis was carried out on an Enraf-Nonius CAD-4 automatic four-circle diffractometer at
20°C. The 1H NMR spectra for solutions in acetone-d6 and DMSO-d6 were taken on a Tesla BW-567 (100 MHz,
HMDS), and 31P NMR spectra on a Bruker WR-80 spectrometer at 32 MHz with 85% H3PO4 as the reference.
The unit cell parameters of colorless monoclinic prisms of C16H24ClN4O5P were: a = 10.312(6),
b = 11.529(5), c = 17.51(1) Å; β = 92.33(6)°; V = 2080(2) Å3; dcalc = 1.25 g/cm3; Z = 4; space group P21/n.
The unit cell parameters and intensities of 4612 reflections were measured, of which 3155 reflections
with I > 3σ were used, employing CuKα radiation (λ = 1.54184 Å), a graphite monochromator, and
ω/2θ-scanning, θ < 74°. No drop in intensity of control reflections was observed during the exposure. An
empirical absorption correction was used µCu = 2.639 mm-1. The structure was solved by the direct method
using the SIR program [4] and refined initially isotropically and then anisotropically. The hydrogen atoms were
found from the electron density difference maps. Their contribution to the structural amplitudes were considered
with fixed positional and isotropic temperature parameters. The final R = 0.052 and Rw = 0.066 were found using
2899 independent reflections. All the calculations were carried out using the MOLEN program package [5] on an
AlphaStation 200 computer. Analysis of the intermolecular interactions and figures of the structures were
obtained using the PLATON program [6]. The atomic coordinates and geometrical parameters are given in
Tables 3-5.
Synthesis of Enamines and Bisenamines 2, 3 (General Procedure). A mixture of aldehyde 1a,b
(0.02 mol) and 3,4-diaminofurazane (0.02 mol) was heated at reflux for 16 h in the corresponding alcohol. The
solvent was removed in vacuum and the crystalline precipitate of 3-amino-4-[(2-dialkoxyphosphoryl)-2-
chloroethenyl-amino)]furazanes 2a,b were filtered off, washed with ethanol, and dried. The yield of 2a was 85%
and the yield of 2b was 87%.
3,4-Bis[(2-dialkoxyphosphoryl)-2-chloroethenylamino]furazanes 3a,b were obtained analogously
from aldehyde 1a,b (0.04 mol) and 3,4-diaminofurazane (0.02 mol) in 78 and 81% yield, respectively.
3H,6H-4-(diisopropoxyphosphoryl)furazano[3,4-b]piperazine Hydrochloride (4). A solution of 2b
(3.25 g, 0.01 mol) in xylene (20 ml) was heated at reflux for 12 h. The solvent was distilled off in vacuum. The
crystalline precipitate of 4 was filtered off, washed with ether, and dried to give 2.7 g (83%).
Diethyl Ester of 2-[(4-Amino-3-furazanyl)amino]-1-chloroethyl-2-hydroxy-1-phenylphosphoric
Acid (5a). A mixture of diethoxyphosphorylphenyl derivative of α-chloroacetaldehyde (5.81 g, 20 mmol) and
3,4-diaminofurazane (2 g, 20 mmol) in acetonitrile (30 ml) was heated at reflux for 12 h. The solvent was
evaporated off and 10 ml 1:1 ether–ethanol was added. The crystalline precipitate was filtered off, dried, and
recrystallized from ethanol to give 6.48 g (83%) of compound 5a.
Diethyl Ester of 2-[(4-Amino-3-furazanyl)amino]-1-chloro-2-ethoxyethyl-1-phenylphosphonic Acid
(5b). A mixture of diethoxyphosphorylphenyl derivative of α-chloroacetaldehyde (5.81 g, 20 mmol) and 3,4-
diaminofurazane (2 g, 20 mmol) in ethanol (30 ml) was heated at reflux for 10 h. The solvent was removed and
10 ml 1:1 ether–acetonitrile was added to the residue. The crystalline precipitate of 5b was filtered off, washed
with ether, and recrystallized from acetonitrile to give 6.7 g (80%).
4-(Diethoxyphosphoryl)-5-ethoxy-4-phenyl-3,4,5,6-tetrahydrofurazano[3,4-b]piperazine (6).
A
solution of 5b in ethanol (10 ml) was added dropwise to a stirred solution obtained from metallic sodium (0.23 g,
10 mmol) in ethanol (20 ml) at 50°C. The reaction mixture was heated at reflux for 8 h. The solvent was
evaporated off and ether (15 ml) was added to the residue. The precipitate of NaCl was filtered off. The filtrate
was evaporated in vacuum. The crystalline precipitate of 6 was filtered off and recrystallized from acetone to
give 2.9 g (76%).
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4-Diethoxyphosphoryl-5-hydroxy-4-phenyl-3,4,5,6-tetrahydrofurazano[3,4-b]piperazine Hydro-
chloride (7). A solution of 5a (3.9 g, 0.01 mol) in toluene (20 ml) was heated at reflux for 8 h. The solvent was
distilled off and 6 ml 1:1 ether–hexane was added to the residue. The crystalline precipitate of 7 was filtered off,
washed with ether, and dried to give 2.7 g (69%).
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A. Altomare, G. Cascarano, G. Giacovazzo, and D. Viterbo, Acta Crystallogr., A47, 744 (1991).
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A. L. Spek, Acta Crystallogr., A46, 34 (1990).
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