Synthesis and X-ray study of novel azofurazan-annulated macrocyclic lactams

Article abstract of DOI:10.1002/jhet.5570420408

Reaction of 1,4-di-(3-aminofurazan-4-oyl)piperazine 4 with dibromoisocyanurate (DBI) affords azofurazan-annulated macrocyclic lactam 7; the X-ray structure of the macrocycle 7 is reported. The synthesis was started with 3-aminofurazan-4-carboxylic acid 1. A one-pot method for preparation of the amino acid was elaborated from commercially available cyanoacetic ester. Amides of the acid have been prepared via the esterification and subsequent amination.

Full text of DOI:10.1002/jhet.5570420408

May-Jun 2005
519
Synthesis and X-ray Study of Novel Azofurazan-annulated
macrocyclic Lactams
Aleksei B. Sheremetev,* Nataliya S. Aleksandrova and Dmitrii E. Dmitriev
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47, Leninsky Prosp., Moscow 119991, RUSSIA
Fax: (internal) +7 (095) 135 5328
E-mail: sab@ioc.ac.ru
Boris B. Averkiev and Mikhail Yu. Antipin
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov Street
B-334, Moscow 117813, RUSSIA
Fax: (internal) +7 (095) 135 5085
E-mail: M_Antipin@yahoo.com
Received September 2, 2004
Reaction of 1,4-di-(3-aminofurazan-4-oyl)piperazine 4 with dibromoisocyanurate (DBI) affords azo-
furazan-annulated macrocyclic lactam 7; the X-ray structure of the macrocycle 7 is reported. The synthesis
was started with 3-aminofurazan-4-carboxylic acid 1. A one-pot method for preparation of the amino acid
was elaborated from commercially available cyanoacetic ester. Amides of the acid have been prepared via
the esterification and subsequent amination.
J. Heterocyclic Chem., 42, 519 (2005).
Introduction.
amide units can be combined together to form multisite
complexing agents, would be of biological interest.
There is considerable current interest in the design of
drugs molecules which combined together natural moieties
with unnatural synthetic blocks. These combinations gen-
erally provide properties ideal for optimal receptor interac-
tion, selective mode of action and clearance from the site
of action. It is well known that piperazine chemistry have
received much attention since the saturated nitrogen hete-
rocycle is an important building block in natural products
and synthetic drugs exhibiting diverse properties.
Macrocycles incorporating the piperazine subunit have
the ability to act as host to both neutral molecules and
ionic species [1]. Photoresponsive azobenzene bridged
piperazine incorporating macrocycles have been shown
to change their cavities by the UV-induced E-Z iso-
merism of the N=N bond [2]. As a result, their binding
ability would be corrected. A few photoresponsive piper-
azine macrocycles have been synthesized by condensa-
tion of 4,4'-bis(bromomethyl)-azobenzene with piper-
azine precursors [2].
We have recently reported the synthesis and activity of
several novel, highly preorganized azofurazan-annulated,
piperazine containing chromophoric macrocycles, when
the furazan ring was directly N-attached to the piperazine
ring [3,4]. The macrocycles closure was a result of N=N
bond formation at oxidative cyclization of the correspond-
ing bis(3-aminofurazan-4-yl) piperazine, a procedure that
has been currently developed by us [3-7] and others [8-12].
Furazan fused to seven-membered lactams have been
synthesized by amide bond formation [13]. No azofurazan
macrocycles containing amide moieties have been pre-
pared. Macrocycles when azofurazan, piperazine, and
Results and Discussion.
In a series of azofurazan-annulated macrocyclic lactam
syntheses, based on the generation and oxidation reac-
tions of bis(3-aminofurazan-4-yl) compounds, the 3-
aminofurazan-4-carboxylic acid 1 served as a key syn-
thetic precursor [7]. This acid 1 was previously synthe-
sized by Longo [14] from malononitrile in six steps in a
9% yield. Because of the recurring use of compound 1
this paper details an alternative advantageous route to
this versatile intermediate. The most attractive seemed
the use of a strategy we recently developed [15-17],
based on the reaction of diverse precursors related to α-
dicarbonyl compounds with hydroxylamine being oxi-
mating, aminating, and redox reagent. We have success-
fully adapted this strategy to the synthesis of the amino
acid 1. As outlined in Scheme 1, commercially available
cyanoacetic ester was converted to cyano oxime (nearly
quantitative yield) by nitrosation with sodium nitrite in
the presence of an acid by a modified literature procedure
[18]. Subsequent treatment with an excess of hydroxy-
lamine hydrochloride and a mixture of NaOH and KOH
with heating and vigorous stirring followed by acidifica-
tion gave the amino acid 1 in 78% yield. The stages are
carried out in one-pot. Esterification of the acid 1 with
HCl/MeOH at refluxing for 7 h was accomplished by for-
mation of the 3-amino-4-carbmethoxyfurazan 2 in 85%
yield. The synthesis of ester 2 was thus achieved in two
steps in an overall yield of 69%, which is a significant
improvement over the previous route.

520
A. B. Sheremetev, N. S. Aleksandrova, D. E. Dmitriev, B. B. Averkiev, and M. Y. Antipin
Vol. 42
Scheme 1
In order to relieve the identification of macrocyclic
furazanamide structures, a series of more ordinary model
amides was synthesized. Thus, an methanolic solution of
the ester 2 and morpholine, thiomorpholine or N-
methylpiperazine under reflux for 5 h gave the morpolide
3a, thiomorpolide 3b, and the piperazide 3c in 47%, 51%,
and 36% yields respectively, together with great recovered
starting material (Scheme 2). It is interesting that refluxing
of the ester 2 and N-methylpiperazine in n-butanol 3-
aminofurazan-4-carboxylic acid n-butyl ester was obtained
in 76% yield. We have found that the amides 3a-c can be
synthesized by employing mild amination conditions, in
which the ester 2 was heated with a slight excess of the
appropriate secondary amine under argon in the absence of
any solvent. The reaction was usually accomplished at
120-130 °C over 1 hour. Yields of the amides 3a-c were ca.
80%.
data supported structure 4. A small amount (12%) of
water soluble salt 5 was separated. It is interesting that
the major product (45%) was tertiary amine 6.
Structure 6 was based on MS, NMR, IR, and micro-
analysis. Thus, the mass spectrum of 6 showed a strong
molecular ion at m/z 420 (100%), which analyzed for
C H N O . The fragment at m/z 390 indicated the
16 24 10
4
loss of NO.
1
Four groups of protons are observed in the H NMR
spectrum of 6, namely one singlet of the amino group at
6.34 ppm, another singlet of bridge CH -groups at 2.7
2
ppm, and two broadened triplets of the piperazine rings
at 3.5 and 3.6 ppm, indicative of a symmetrical struc-
13
ture. Comparison of the C NMR spectral data for
compound 6 with its analog 3c showed that they are
similar, in agreement with the presence of the tertiary
amine fragment.
Scheme 2
2
3a (X = O)
3b (X = S)
3c (X = NMe)
Treatment of diamine 4 with dibromoisocyanurate (DBI)
The IR spectra of compounds 3a-c exhibit a band at ca.
-1
in CH Cl at room temperature, according to our recently
1650 cm , typical of the carbonyl group in amides and a
2
2
-1
reported method [6] led to a brown-red slurry (Scheme 4).
After 5 h the presence of 4 was no longer detectable and a
solution of macrocycles 7 and 8 was easily colleted by fil-
tration from cyanuric acid, which is the product of the
transformation of DBI. The solvent was removed under
reduced pressure and the crude residue separated by flash
column chromatography (SiO , typically 5:1 CHCl -
pair of bands at ca. 3320 and 3420 cm , typical for the
1
amino group attached to the furazan ring. The H NMR
spectra show two methylene resonances and a singlet at ca.
6.3 ppm, which is characteristic of the amino group [19].
13
In the C NMR spectrum, the low field signal at ca. 157
ppm was assigned to the amide carbon atom [20]. Two sig-
nals, at ca. 156 ppm from quanternary C-NH and at ca.
2
3
2
CH CN) to give the 12-membered lactam 7 as the major
product (55%), together with a small amount of the 24-
membered lactam 8 (0,5%).
141 ppm from second furazanic carbon, were also
observed.
On the other hand, the reaction of ester 2 with piper-
azine was more complex and three compound were iso-
lated (Scheme 3). Desired diamide 4 (35%) was
obtained as a poorly soluble white solid whose spectral
3
Treatment of diamine 6 with DBI, carried out in CH Cl ,
2
2
according to above method, led to a brown-red slurry,
which was hard to separate.

May-Jun 2005
Synthesis and X-ray Study of Novel Azofurazan-annulated macrocyclic Lactams
521
Scheme 3
Scheme 4
7
8
Lactams 7 and 8 are red orange crystals with high
melting points, soluble in warm polar organic solvents
and insoluble in water. The electron impact mass spectra
of 7 and 8 showed the expected molecular ions at m/z
304 and m/z 608, respectively, and significant peaks due
plane of neighboring amide fragment equal to 74.32(7)°
for C(9)-N(10)-O(11)-N(12)-C(13) and C(8)-O(7)-N(4)-
C(3)-C(5), and to 52.07(6)° for C(16)-N(17)-O(18)-N(19)-
C(20) and C(21)-O(22)-N(1)-C(2)-C(6). Due to these large
values of dihedral angles there is no conjugation between
furazan rings and the amide fragments, and the C(8)-C(9)
and C(20)-C(21) bonds demonstrate standard bond length
for single C-C bond (1.506(2) Å).
The geometry of azofurazan moiety in molecule 7 is
similar to the geometry of this fragment in macrocycle 9,
studied by us earlier [6]. The bond lengths of this frag-
ment in molecule 7 are presented in caption to Figure 1. It
is worth mentioning that the lengthening of internal N-O
bonds (N(12)-O(11) and N(17)-O(18)) in comparison
with external N-O bonds (N(10)-O(11) and N(19)-O(18))
is about 0.03 Å. In contrast to the macrocycle 9 [6], in
molecule 7 the azofurazan moiety is more planar; the tor-
+
+
to loss of one (M - 30) and two NO (M - 60) from the
molecular ions. The IR spectra of 7 and 8 were similar
-1
and exhibited C=O stretches at ca. 1650 cm . It is
1
important to note, we were unable to measure the H and
13
C NMR spectra of 7 due to broad lines possibly caused
by dynamic processes.
The structural assignment was unequivocally confirmed
by the X-ray crystallographic study of 12-membered lac-
tam 7. In the Figure 1 molecule 7 is presented in two ori-
entations to show clearly conformation of the azofurazan
and the piperazine moieties and their mutual arrangement.
The dihedral angle between plane of the furazan ring and

522
A. B. Sheremetev, N. S. Aleksandrova, D. E. Dmitriev, B. B. Averkiev, and M. Y. Antipin
Vol. 42
a
b
Figure 1. The general view of molecule 7. Two projections of the molecule, demonstrating conformations of azofurazan and piperazine fragments and
their mutual arrangement are shown. Displacement ellipsoids for view a are drawn at the 50% probability level. The view b is represented as a "ball and
stick" model for clarity. The bond lengths for azofurazan fragment (Å): C(9)-N(10) 1.301(2), C(9)-C(13) 1.423(2), N(10-O(11) 1.391(2), O(11)-N(12)
1.358(2), N(12)-C(13) 1.308(2), C(13)-N(14) 1.407(2), N(14)-N(15) 1.244(2), N(15)-C(16) 1.409(2), C(16)-N(17) 1.299(2), C(16)-C(20) 1.425(2),
N(17)-O(18) 1.367(2), O(18)-N(19) 1,395(2), N(19)-C(20) 1.296(2).
sion angles N(12)-C(13)-N(14)-N(15) and N(14)-N(15)-
C(16)-N(17) are -179.8(2) and 18.9(2)° respectively,
while in molecule 9 they are equal to 167 and 32°. The
angle between two planes of the furazan rings is 16.51(8)
in 7 and 20.9° in 9. This difference in planarity is evi-
dently a result of smaller size of macrocycle 9 in compar-
ison with 7 (10 versus 12).
as a chair [24]. In this structure 10 the piperazine ring is
incorporated in the 15-membered macrocycle like in our
case (Figure 2). The Cremer & Pople puckering parame-
ters for compound 10 are Q = 0.75, θ = 89°, ϕ = 2°, hence,
the conformation is a boat. Because the nitrogen atoms of
the piperazine ring in macrocycle 7 are also included in
amide groups, they have planar geometry. The internal
piperazine bond angles at N(1) and N(4) are increased to
112.0(1) and 115.8(1)° respectively.
Despite of somewhat higher density of crystals 7, no
shortened intermolecular contacts or peculiarities of crys-
tal packing were found.
EXPERIMENTAL
Melting points were determined on Gallenkamp melting point
apparatus and they are not corrected. Infrared spectra were deter-
mined in KBr pellets on a Perkin-Elmer Model 577 spectrometer.
Mass-spectra were recorded on a Varian MAT-311A instrument.
9
10
Figure 2. Macrocycles 7 and 10.
1
13
H NMR spectra were recorded at 300 MHz and C spectra at
75 MHz on a Bruker AM-300 instrument. Chemical shifts for
1
13
both H NMR and C NMR are referred to chemical shifts for
solvent (for DMSO-d it is 2.50 ppm and 39.51 ppm for proton
6
Due to incorporation into the macrocycle, the piperazine
ring adopts an unusual twist conformation. The atoms C(2)
and C(3) deviate from the least square plane of the other
four atoms (mean deviation 0.08 Å) by 1.202(2) and
0.847(3) Å respectively. The Cremer & Pople puckering
parameters, calculated by RICON program [22] are Q =
0.74, θ = 85°, ϕ = 26°. Our analysis of the 157 piperazine
fragments found in the Cambridge Crystallographic
Database [23] revealed only one analogues fragment (CSD
refcode QUJDOO), which conformation is not described
and carbon NMR, respectively). All separations were carried out
under flash chromatography condition on silica gel. Analytical
thin layer chromatography (TLC) was conducted on precoated
silica gel plates ( Silufol F ).
254
Crystallographic Data for Macrocycle (7).
Crystallographic data was acquired at 298 K, crystals of com-
pound 7 are triclinic, space group P-1, a = 6.517(3) Å, b = 9.323(4)
Å, c = 10.203(5) Å, α = 92.06(4)°, β = 105.57(4), γ = 93.48(4), V
3
-3
= 595.2(5) Å , Z = 2, M = 304.24, d = 1.697 g•cm , µ(Mo-K )
calc
α
-1
= 0.137 mm , F(000) = 312. Intensities of 3774 reflections were

May-Jun 2005
Synthesis and X-ray Study of Novel Azofurazan-annulated macrocyclic Lactams
523
measured with a Siemens P3/PC diffractometer at 293K [λ(Mo-
K ) = 0.71071 Å, θ/2θ scanning, 2θ < 60°], and 3484 independent
Anal. Calcd. for C H N O (198.18): C, 42.42; H, 5.09; N,
7 10 4 3
28.27. Found: C, 42.47; H, 5.13; N, 28.25.
α
reflections (R = 0.0426) were used in further refinement. The
int
Method 2.
structure was solved by direct methods and refined by full-matrix
2
A mixture of ester 2 (1.4 g, 10 mmol) and morpholine (0.87 g,
10 mmol) was stirred at 120-130 °C for 1 h under nitrogen. On
cooling to room temperature a white solid was obtained. The
least squares against F in the anisotropic approximation for the
non-hydrogen atoms. All hydrogen atoms were located from the
difference electron density synthesis and were refined isotropi-
solid was washed with CHCl and recrystallized from propanol-2
cally. The refinement converged to wR = 0.1423 and GOF =
3
2
to yield the product 3a in 93% yield.
The following amides were prepared by the same methods as
for 3a.
1.037 for all independent reflections [R = 0.0472 was calculated
1
against F for 2390 observed reflections with I > 2σ(I)]. All calcula-
tions were performed using SHELXTL program package [25].
Atomic coordinates, atomic anisotropic displacement parameters,
bond lengths and bond angles have been deposited at the
Cambridge Crystallographic Data Center as supplementary publi-
cation numbers 258586.
4-(3-Aminofurazan-4-oil)thiomorpholine (3b).
This compound has the following properties: mp 112-113 C;
ir: 3408, 3320, 2928, 1640, 1560, 1512, 1448, 1288, 1164, 992,
-1
1
956, 848 cm ; H nmr (DMSO-d ): 3.64 (bs, 4H), 3.68 (bs, 4H),
6
3-Aminofurazan-4-carboxylic acid (1).
13
6.36 (s, 2H, NH ). C nmr (DMSO-d ): 42.3, 46.9 (OCH ),
2
6
2
65.7, 66.1 (NCH ), 141.3 (C-CO H), 156.1 (C-NH ), 157.1
To a stirred emulsion of ethyl cyanoacetate (56.6 g, 0.5 mol)
and sodium nitrite (34.5 g, 0.5 mol) in a mixture of EtOH (35 ml)
and water (400 ml) was added dropwise 85% H PO (20 ml) at
2
2
2
+
(C=O). ms: (m/z) 198 (M ).
Anal. Calcd. for C H N O (198.18): C, 42.42; H, 5.09; N,
7
10 4 3
3
4
28.27. Found: C, 42.47; H, 5.13; N, 28.25.
25-30 °C. After 1 h, the mixture was cool to 10 °C, stirred for a
further 12 h and treated with sodium hydroxide (4×20 g, 2 mol)
and potassium hydroxide (2×28 g, 1 mol). To the resulting solu-
1-Methyl-4-(3-aminofurazan-4-oil)piperazine (3c),
This compound has the following properties: mp 100-101 °C;
tion NH OH•HCl (139 g, 2 mol) was slowly added at room tem-
2
1
H nmr (DMSO-d ): 2.24 (s, 3H), 2.52 (t, J=4.6 Hz, 4H), 3.68 (t,
perature. The mixture was heated to 95-100 °C, stirred for 2 h,
cooled to ambient temperature and quenched with conc. HCl to
pH 1. Precipitation occurred on cooling to 0-5 °C for 6 h and the
precipitate was collected by filtration and dried. The filtrate was
extracted with diethyl ether (3×60 ml). The combined organic
extracts were evaporated under reduced pressure. The residue
was combined with the precipitate and recrystallized from hot
6
13
J=4.6 Hz, 4H), 6.37 (s, 2H, NH ). C nmr (DMSO-d ): 41.9,
2
6
46.5 (CONCH ), 45.5 (Me), 54.0, 54.7 (MeNCH ), 141.5 (C-
2
2
+
CO H), 156.2 (C-NH ), 157.1 (C=O). ms: (m/z) 211 (M ).
2
2
Anal. Calcd. for C H N O (211.22): C, 45.49; H, 6.20; N,
8
13 5 2
33.16. Found: C, 45.58; H, 6.16; N, 33.09.
Quaternary Salt, 1-Benzyl-1-methyl-4-(3-aminofurazan-4-
oil)piperazinium Chloride.
water to give the title compound 1 (101 g, 78%) as white solid,
1
mp 214-215 °C (lit. mp 213-214°C [21], 216-217°C [14]);
H
13
This compound has the following properties: mp 238-240 °C;
nmr (DMSO-d ): 6.31 (s, 2H, NH ), 9.1 (b, 1H). C nmr
6
2
1
H nmr (DMSO-d ): 3.11 (s, 3H, Me), 4.00, 4.35 (bs, 8H, NCH ),
(DMSO-d ): 140.4 (C-CO H), 156.8 (C-NH ), 160.5 (C=O).
6
2
6
2
2
13
4.82 (2H, CH Ph), 6.46 (2H, NH ), 7.55 (m, 5H, Ph). C nmr
2
2
3-Amino-4-carbmethoxyfurazan (2).
(DMSO-d ): 36.0, 40.5 (CONCH ), 45.4 (Me), 58.0, 58.3
6
2
+
(N CH ), 67.2 (CH Ph), 127.3 (i-Ph), 129.1 (m-Ph), 130.6 (p-
HCl gas was bubbled through a solution of acid 1 (129 g, 1
2
2
Ph), 133.4 (o-Ph), 141.1 (C-CO H), 156.2 (C-NH ), 157.6
mol) in methanol (300 ml) at refluxing for 7 h. The solvent was
2
2
(C=O).
Anal. Calcd. for C
N, 20.79. Found: C, 53.50; H, 5.71; N, 20.77.
removed and the residue diluted with CH Cl (500 ml) and
washed with water (100 ml), NaOH (0.1 M, 2×50 ml) and finally
with water (2×70 ml). Removal of the dried solvent gave color-
2
2
H
N O Cl (336.80): C, 53.49; H, 5.69;
5 2
15 19
less solid which was recrystallized from CHCl to give ester 2
3
3-Aminofurazan-4-carboxylic Acid n-Butyl ester.
1
(122 g, 85%), mp 154-155 °C; H nmr (acetone-d ): 3.97 (s, 3H,
6
13
To a stirred solution of ester 2 (1.4 g, 10 mmol) in n-butanol
(25 ml) N-methyl piperazine (1.1 g, 11 mmol) was added in one
portion under nitrogen. The mixture was refluxed for 6 h. The
solvent was removed and the residue washed with water (325 ml)
OMe), 6.00 (s, 2H, NH ). C nmr (acetone-d ): 53.5 (OCH ),
2
6
3
140.2 (C-CO H), 157.5 (C-NH ), 160.6 (C=O). ms: (m/z) 143
2
2
+
+
(M ), 113 (M - NO).
Anal. Calcd. for C H N O (143.10): C, 33.57; H, 3.52; N,
4
5 3 3
and crystallized from water to give the product (76%) as a white
29.36. Found: C, 33.62; H, 3.54; N, 29.33.
4-(3-Aminofurazan-4-oil)morpholine (3a).
Method 1.
1
solid: mp 73-74 °C; H nmr (CDCl ): 0.95 (t, J=6.4 Hz, 3H), 1.46
3
(m, 2H, CH ), 1.76 (m, 2H, CH ), 4.41 (t, J=6.1 Hz, 2H, CH )
2
2
2
13
5.13 (s, 2H, NH ). C nmr (CDCl ): 13.5 (Me), 18.9 (CH Me),
2
3
2
30.3, 66.6 (OCH ) 138.6 (C-CO H), 155.9 (C-NH ), 159.7
2
2
2
To a stirred solution of ester 2 (1.4 g, 10 mmol) in methanol
(15 ml) morpholine (0.96 g, 11 mmol) was added in one portion
under nitrogen. The mixture was refluxed for 6 h. The solvent
was removed and the residue separated by chromatography (sil-
ica gel, 5% CH CN/CHCl ) to give amide 3a as a white powder:
+
(C=O). ms: (m/z) 185 (M ).
Anal. Calcd. for C H N O (185.18): C, 45.40; H, 5.99; N,
7
11 3 3
22.69. Found: C, 45.43; H, 6.10; N, 22.65.
1,4-Di-(3-aminofurazan-4-oyl)piperazine (4).
Method 1.
3
3
1
mp 136-138 °C (MeOH); H nmr (DMSO-d ): 3.64 (bs, 4H),
6
13
3.68 (bs, 4H), 6.36 (s, 2H, NH ). C nmr (DMSO-d ): 42.3, 46.9
2
6
(OCH ), 65.7, 66.1 (NCH ), 141.3 (C-CO H), 156.1 (C-NH ),
157.1 (C=O). ms: (m/z) 198 (M ), 168 (M - NO).
To a stirred solution of ester 2 (1.4 g, 10 mmol) in methanol
(40 ml) anhydrous piperazine (0.43 g, 5 mmol) was added in one
2
2
2
2
+
+

524
A. B. Sheremetev, N. S. Aleksandrova, D. E. Dmitriev, B. B. Averkiev, and M. Y. Antipin
Vol. 42
+
portion under nitrogen. The mixture was refluxed for 24 h until
starting product spot could not be detected by TLC. On cooling, a
white solid gradually precipitated from the reaction mixture. The
orange crystals: mp 243-245 °C (CHCl ); ms: (m/z) 304 (M ),
3
+
+
274 (M - NO), 245 (M - 2NO), 219, 191, 165, 136, 124, 97, 84;
ir: 1656 (C=O), 1548 (C=N), 1492, 1456, 1428, 1280, 1160,
–1
solid was collected by filtration and washed with CH Cl (2×30
1092, 1028, 1000 (C=N), 894 cm .
2
2
ml) and water (2×25 ml) to afford the crude product (mp 292-294
°C) which was recrystallized from ethanol. The title compound 4
(0.17 g, 11%) was obtained as a white powder: mp 312-314 °C;
ir: 3420, 3320, 1728, 1616, 1548, 1508, 1460, 1444, 1416, 1364,
Anal. Calcd. for C H N O (304.22): C, 39.48; H, 2.65; N,
36.83. Found: C, 39.50; H, 2.69; N, 36.81.
10 8 8 4
The second fraction, 24-membered lactam 8 (0.0076 g, 0.5%)
was obtained as yellow-orange powder: mp 335-339 °C; ms:
-1
+
+
1
1288, 1180, 996, 888, 860, 780 cm ; H nmr (DMSO-d ): 3.82
(m/z) 608 (M ), 578 (M - NO). Calcd for C H N O is
608.45.
6
20 16 16 8
13
(s, 8H, CH ), 6.24 (bs, 4H, NH ). C nmr (DMSO-d ): 52.6
2
2
6
(CH ), 141.0 (C-CO), 155.9 (C-NH ), 157.2 (C=O). ms: (m/z)
308 (M ), 292, 261, 251, 224, 196, 166, 112, 84.
2
2
Acknowledgements.
+
Anal. Calcd. for C N O (308.26): C, 38.96; H, 3.92; N,
36.35. Found: C, 39.02; H, 3.95; N, 36.34.
H
The authors are thankful to the International Science
Foundation (grants MM9000 and MM9300) and the Russian
Foundation for Basic Research (grants 98-03-33024a and 00-15-
97359) for financial support.
10 12
8 4
The filtrate was extracted with CH Cl (2×30 ml). The organic
2
2
layer was washed with H O, dried over MgSO , concentrated in
2
4
vacuo and purified by crystallization from 2-propanol to give com-
pound 6 (0.44 g, 21%) as a white powder: mp 125-127 °C; ir: 3395
(NH), 3300 (NH), 3205, 3105, 2970, 2740 (CH), 2680, 1690
(C=O), 1560 (C=N), 1510 (C=N), 1450, 1360, 1310, 1210, 1190
REFERENCES AND NOTES
[1] J. Huuskonen, J. Schulz and K. Rissanen, Liebigs Ann., 1515
(1995) and references therein.
[2] J. Huuskonen, J. Schulz, E. Kolehmainen and K. Rissanen,
Chem. Ber., 127, 2267 (1994).
[3] A. B. Sheremetev, V. O. Kulagina, I. L. Yudin and N. E.
Kuzmina. Mendeleev Commun., 112 (2001).
[4] A. B. Sheremetev, V. L. Betin, I. L. Yudin, V. O. Kulagina, Yu.
V. Khropov, T. V. Bulargina, and A. Y. Kots, Pat. Russia 2167161 (2000);
authors provide Chem. Abstr. 138, 55967 (2003).
[5] A. B. Sheremetev and O. V. Kharitonova, Mendeleev
Commun., 157 (1992).
[6] A. B. Sheremetev, E. V. Shatunova, B. B. Averkiev, D. E.
Dmitriev, V. A. Petukhov and M. Yu. Antipin. Heteroatom Chem., 15,
131 (2004) and references therein.
-1
1
(CO), 1145, 1060, 1020, 940 (C=N), 860 cm ; H nmr (DMSO-
13
d ): 2.73 (m, CH ), 3.57 (m, CH ), 6.37 (s, NH ); C nmr (DMSO-
6
2
2
2
d ): 43.1, 44.2, 45.1, 45.9, 47.9 (CH ), 141.6 (C-CO), 155.9 (C-
6
2
+
+
NH ), 156.8 (C=O). ms: (m/z) 419 [M - H], 361 [M - 2NO + H],
308 [M - H N-F-CO], 224 [H N-F-CON(CH CH )NCH CH ],
210 [H N-F-CON(CH CH )NCH ], 197 [HN(CH CH ) -
2
+
+
2
2
2
2
2
2
+
2
2
2
2
2
2 2
+
+
NCH CH N(CH CH )N ], 181, 152, 112 [H N-F-CO ], 84 [H N-
2
2
2
2
2
2
+
F ] (where F is furazan ring).
Anal. Calcd. for C N O (420.43): C, 45.71; H, 5.75; N,
16 24 10 4
H
33.32. Found: C, 45.79; H, 5.83; N, 33.29.
The water layer was concentrated in vacuo and purified by
crystallization from aqueous propanol-2 to gave the salt 5 (0.57
g, 35%) as a white powder: mp 186-187 °C; ir: 3420-3410, 3320-
3310, 3150-2970, 2650-2610, 2470-2430, 1640, 1560, 1350,
[7] A. B. Sheremetev, N. N. Makhova and W. Friedrichsen, Adv.
Heterocycl. Chem., Academic Press, 78, 65 (2001).
-1
1
1220, 980, 800 cm ; H nmr (DMSO-d ): 3.25 (bs, 4H, CH )
6
2
[8] M. A. Epishina, N. N. Makhova, L. V. Batog, L. S.
Konstantinova and L. I. Khmelnitskii, Mendeleev Commun., 102 (1994).
[9] V. E. Eman, M. S. Sukhanov, O. V. Lebedev, L. V. Batog, L. S.
Konstantinova, V. Yu. Rozhkov and L. I. Khmelnitskii, Mendeleev
Commun., 66 (1996).
3.93 (bs, 4H, CH ), 5.16 (NH ), 6.13 (NH ), 6.29 (NH + OH).
2
2
2
13
C nmr (DMSO-d ): 42.3 (CH ), 42.8 (CH ), 141.0 (C-CO),
6
2
2
144.5 (C-CO), 156.1 (C-NH ), 156.4 (C-NH ), 157 (b, C=O).
2
2
Anal. Calcd. for C
H N O (326.27): C, 36.81; H, 4.32; N,
10 14 8 5
[10] L. V. Batog, L. S. Konstantinova, O. V. Lebedev and L. I.
Khmelnitskii, Mendeleev Commun., 193 (1996).
34.34. Found: C, 36.82; H, 4.48; N, 34.25.
Method 2.
[11] L. V. Batog, L. S. Konstantinova, V. E. Eman, M. S.
Sukhanov, A. S. Batsanov, Yu. T. Struchkov, O. V. Lebedev and L. I.
Khmelnitskii, Khim. Geterotsikl. Soedin., 406 (1996) (in Russian) [Chem.
Heterocycl. Compounds., (Engl. Transl.), 32, 352 (1996)].
[12] V. A. Eman, M. S. Sukhanov, O. V. Lebedev, L. V. Batog, L. S.
Konstantinova, V. Yu. Rozhkov, M. O. Dekaprilevich, Yu. T. Struchkov
and L. I. Khmelnitskii, Mendeleev Commun., 5 (1997).
[13] E. I. Ivanov, A. A. Yavolovskii, E. A. Kuklenko, O. S.
Timofeev, R. Yu. Ivanova and L. V. Grishuk, Zh. Org. Khim., 29, 400
(1993) (in Russian).
A mixture of ester 2 (1.4 g, 10 mmol) and anhydrous piper-
azine (0.43 g, 5 mmol) was stirred at 120-130 °C for 30 min
under argon. On cooling to room temperature a white solid was
obtained. The solid was washed with CH Cl and then dissolved
2
2
in DMSO followed by the addition of water which precipitated
the crude product. After the recrystallization from propanol-2 the
product 4 was obtained in 35% yield, mp 312-314 °C. The
CH Cl layer was concentrated in vacuo and a residue was puri-
2
2
[14] G. Longo, Gazz. Chim. Ital., 61, 575 (1931).
[15] A. B. Sheremetev and E.V. Mantseva, Mendeleev Commun.,
246 (1996).
fied by crystallization from propanol-2 to give compound 6
(45%) as a white powder: mp 125-127 °C.
Macrocycle (7).
[16] A. B. Sheremetev and I. V. Ovchinnikov, Heteroatom Chem.,
8, 7 (1997).
A suspension of the diamine 4 (1.54 g, 5 mmol) and DBI (5.74
g, 20 mmol) in CH Cl (80 mL) was stirred vigorously for 5 h. The
reaction mixture was filtered to remove cyanuric acid. The filtrate
was concentrated in vacuo to give a crude orange mixture of com-
pounds 7 and 8. The products were separated by silica gel flash
column chromatography using CHCl -CH CN (5:1) as eluent.
[17] A. B. Sheremetev, Mendeleev Commun., 135 (1998).
[18] C. O. Parker, Tetrahedron, 17, 109 (1962).
[19] D. E. Dmitriev, Yu. A. Strelenko and A. B. Sheremetev, Izv.
AN, Ser. Khim., 277 (2002) [Russ. Chem. Bull. (Engl. Transl.), 51, 290
(2002)].
2
2
[20] Yu. A. Strelenko, A. B. Sheremetev and L. I. Khmelnitskii,
Khim. Geterotsikl. Soedin., 1101 (1992) [Chem. Heterocycl. Compounds.,
3
3
The first fraction, compound 7 (0.84 g, 55%) was obtained as

May-Jun 2005
Synthesis and X-ray Study of Novel Azofurazan-annulated macrocyclic Lactams
525
(Engl. Transl.), 28, 927 (1992)].
[23] F. H. Allen, Acta Cryst., B58, 380 (2002).
[21] H. Wieland, Z. Kitasato and S. Utzino, Liebigs Ann., 478, 43
(1930).
[24] S. Mahboobi, I. Dechant, H. Reindl, H. Pongratz, A. Popp and
D. Schollmeyer, J. Heterocyclic Chem., 37, 307 (2000).
[22] A. Yu. Zotov, V. A. Palyulin and N. S. Zefirov, J. Chem.
Inform. Comp. Science, 37, 766 (1997).
[25] G. M. Sheldrick (1998). SHELXTL v. 5.10, Structure
Determination Software Suite, Bruker AXS, Madison, Wisconsin, USA.