3-(1-Adamantyl)furazans

Article abstract of DOI:10.1007/s10593-013-1385-z

The reactivity of 3-(1-adamantyl)-4-aminofurazan was studied. Upon treatment with oxidizing reagents the amino group is oxidized to azo, azoxy, and nitro groups. The nitration of 3-(1-adamantyl)-4-aminofurazan with nitric acid provided the corresponding n

Full text of DOI:10.1007/s10593-013-1385-z

Chemistry of Heterocyclic Compounds, Vol. 49, No. 9, December, 2013 (Russian Original Vol. 49, No. 9, September, 2013)
3-(1-ADAMANTYL)FURAZANS
A. B. Sheremetev1*, A. M. Kozeev1, N. S. Aleksandrova1,
M. I. Struchkova1, and K. Yu. Suponitsky2
The reactivity of 3-(1-adamantyl)-4-aminofurazan was studied. Upon treatment with oxidizing reagents the
amino group is oxidized to azo, azoxy, and nitro groups. The nitration of 3-(1-adamantyl)-4-aminofurazan
with nitric acid provided the corresponding nitroamine. The reaction of 3-(1-adamantyl)-4-nitrofurazan
with nitrating and bromination agents takes place at the bridgehead position of the adamantane
fragment and gives the corresponding nitroxyl and bromo derivatives. An X-ray structural analysis of
4,4′-di(1-adamantyl)azofurazan was undertaken.
Keywords: adamantanes, furazans, electrophilic reactions, X-ray structural analysis.
The synthesis and investigation of compounds in which an adamantane framework is attached to a
heterocycle is one of the most active directions in the chemistry of adamantane [1-5]. The geometry and
lipophilicity of adamantane are extremely favorable for its transport through biological membranes and have
been used widely for the creation of biologically active compounds [6-9]. In particular, a series of adamantane
derivatives of 1,2,4- [10-13], 1,3,4- [14-21], and 1,2,5-oxadiazole [7, 22-26] having bactericidal, anti-
inflammatory, and antidiarrheal activity and also agents for the treatment of Alzheimer's disease have been
obtained.
Despite the fact that the adamantyl derivatives of isomeric oxadiazoles are of potential interest the
chemical properties of such compounds have barely been studied at all. There are no published data on the
insertion of substituents into an adamantane fragment attached to an oxadiazole ring. The most effective method
for modification of the adamantane fragment is electrophilic substitution [27, 28]. In this communication, we
disclose investigations of (1-adamantyl)-1,2,5-oxadiazole modifications via electrophilic substitution.
It should be noted that 1,2,5-oxadiazole (furazan) is a highly electron-deficient aromatic heterocycle due
to the presence of three heteroatoms [29, 30]. For this reason, the reactivity of molecules containing a furazan
substituent toward electrophilic reagents is greatly reduced [31-33]. On the other hand, the bulky adamantyl
fragment at the ortho position to the second substituent in the furazan ring can affect the reactivity of this
substituent. It was on account of these facts that the present investigation was undertaken.
_______
*To whom correspondence should be addressed, e-mail: sab@ioc.ac.ru.
1N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Ave., Moscow
119991, Russia.
2A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilova St.,
Moscow 119991, Russia; e-mail: kirshik@yahoo.com.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1457-1468, September, 2013.
Original article submitted July 12, 2013.
1358
0009-3122/13/4909-1358©2013 Springer Science+Business Media New York

As starting material, we used 3-(1-adamantyl)-4-aminofurazan (1) [26], which contains the least
electron-withdrawing aminofurazanyl fragment (Taft induction constant σ* 2.55 [34]).
We had previously developed a method for the oxidation of aminofurazans to nitrofurazans with the
mixtures based on H2O2 containing H2SO4, NaWO4, and other inorganic additives [35]. Attempts to use these
mixtures for oxidation of the amine 1 proved ineffective: not only the amine 1 did not dissolve in the aqueous
oxidizing mixtures, but it is not even at all wetted, which prevented the reaction. The reaction with employment
trifluoroperacetic acid as organic solvent, which has also been used for the oxidation of aminofurazans [36, 37],
proved to be more effective. Oxidation usually requires no more than 3 hours [38, 39] at 15°C (the usual
conditions) to complete, however in our case the reaction mixture remained blue, indicating the presence of an
intermediate nitroso compound, even after 24 h. In the present case oxidation is probably prevented due to the
steric hindrance. However, it is possible to bring the reaction to completion by refluxing the reaction mixture;
the color disappears completely after reflux for an hour. It should be noted that the adamantane framework can
undergo oxidative degradation during the action of peracids, giving polar oxygen-containing products [40]. In
fact, according to TLC, polar products are also formed in the reaction mixture together with the low-polarity
compounds 2 and 3 (Rf 0.71 and 0.27, respectively, eluent 1:1 hexane–CHCl3). When the reaction mixture is
washed these substances pass into the aqueous phase. After chromatographic separation of the substances
present in the organic phase, 3-(1-adamantyl)-4-nitrofurazan (2) and 4,4'-di(1-adamantyl)azoxyfurazan (3) were
isolated with yields of 32 and 7%. Attempts to isolate individual products from the aqueous phase were
unsuccessful.
O
NO2
N+
N
+
N
N
N
N
N
N
N
(CF3CO)2O
H2O2, CH2Cl2 , 1 h
15°C, 2 h
O
O
N
O
2
3
KMnO4, HCl
H2O, CCl4
NH2
room temp., 2 h
N
N
N
N
N
N
O
O
O
1
4
It is known [41-46] that oxidation of aminofurazans by one-electron oxidizing agent, such as KMnO4, in
hydrochloric acid usually gives good yields of the corresponding azofurazans. This reagent also proved
effective in the case of the amine 1; oxidation in the two-phase CCl4–H2O system took 2 h, and the azo product
was formed in 81% yield.
The amine 1 was not changed during the attempts of bromination in CCl4, while an inseparable mixture
of products was formed when it was refluxed in bromine in the presence of AlCl3 [47] or AlBr3 [48]. When a
KBr–NaNO3–CF3CO2H mixture was used for mild oxidative bromination of adamantanes [49] the adamantane
framework of compound 1 was not affected, and decomposition of the furazan ring was observed. Four products
were isolated from the reaction mixture: 2-(1-adamantyl)-2-bromo-2-nitroacetonitrile (5) (15%); adamantane-
1-carbonitrile (6) (11%); 2-(1-adamantyl)-2-hydroxyiminoacetonitrile (7) (18%); adamantane-1-carboxylic acid
(8) (14%). A similar type of ring cleavage is characteristic for aminofurazans under diazotization conditions [30,
50, 51].
KBr
NaNO3
Br
1
+
+
+
CN
NO2
N
CF3COOH
room temp.
3 days
CO2H
CN
OH
CN
8
5
6
7
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The problems arising during bromination are probably due to the presence of the amino group in
compound 1. Although it contains the more electron-withdrawing nitrofurazan fragment (Taft induction
constant σ* 2.88 [34]) compound 2 can actually be fully brominated with the Br2–AlCl3 mixture in 2 h. It should
be noted that under these conditions [47, 48] four bromine atoms may be substituted in reaction with
unsubstituted adamantane, however only monobromination occurs with compound 2. Compound 9 was isolated
in a 62% yield, while 1,3-dibromoadamantane (10) was formed as a side product (19%).
NO2
Br2, AlCl3 (cat.)
Br
2
+
, 2 h
room temp., 16 h
Br
Br
N
N
O
9
10
There are several potential centers capable of reacting with nitrating reagents in the structure of the
amine 1. On the one hand, it is known [52-57] that the amino group in the furazan ring can be converted into a
nitramino group, and on the other, nitro [58-60] or nitroxy [61] groups can be inserted in the adamantane
framework. If the amine 1 is treated with concentrated nitric acid at 0°C selective N-nitration can occur, and the
nitramine 11 is formed in a 78% yield. If 56% nitric acid is used the yield of the product 11 is reduced to 11%,
while the use of HNO3–H2SO4, HNO3–CF3CO2H, and HNO3–(CF3CO)2O mixtures at temperatures between 10
and 50°C give mixtures that according to TLC contain more than 10 products.
H
N
NO2
HNO3
1
0–5°C, 20 min
N
N
O
11
As in the case of bromination, nitration of the derivative 2 takes place in a more well-defined manner.
Whereas the reaction does not occur at room temperature, if compound 2 is heated in concentrated nitric acid at
40°C nitroxylation of adamantane is complete after 1.5 h. After dilution of the reaction mixture with water,
extraction, and chromatographic purification, the nitrate ester 12 was obtained in a 55% yield. The
hydroxyadamantane 13 (yield 18%), formed during isolation of compound 12 as a result of hydrolysis, was
isolated as a side product.
NO2
NO2
HNO3
O2NO
HO
2
+
room temp., 1.0 h
40°C, 1.5 h
N
N
N
N
O
O
12
13
The structure of the synthesized adamantylfurazans was confirmed by elemental analysis, IR and NMR
spectroscopy, and EI mass spectrometry (Table 1). An X-ray structural analysis was undertaken for compound 4
(Fig. 1).
The mass spectra of most of the compounds contain signals for the low-intensity molecular ions, while
the signal of the most intense ion corresponds to the adamantyl radical. The fragmentation under EI arises from
the functional groups that are present. Thus, in the case of the nitro derivative 2 and the nitramine 11 the nitro
group is removed first, and [M-NO2]+ ions are formed. For the nitro derivative 10, which contains a
bromoadamantyl fragment, although the low-intensity [M-NO2]+ ion is recorded the main direction of
fragmentation results from loss of bromine, and the strongest ion is [M-Br]+. For the azoxy compound 3 loss of
the oxygen of the azoxy group with formation of the ion [M-O]+ is the primary dissociation event during EI.
1360

A characteristic feature for the nitrofurazans 2, 10, 12, and 13 is the presence in the 14N NMR spectra of
13
a narrow (∆ν1/2 = 18-25 Hz) singlet for the nitrogen atom of the nitro group at 30.3-32.8 ppm. In the C NMR
spectra the signal of the carbon atom attached to the nitro group is greatly broadened as a result of 13C–14N
coupling, which facilitates assignment of the signals. The JMODXH.AU software, with which it is possible to
distinguish between the signals of the CH, CH2, and CH3 groups and the quaternary carbon atoms, and the data
1
from two-dimensional H–13C heteronuclear correlation spectra through one bond (HMQC) and through 2-3
bonds (HMBC) were used for assignment of the signals in the 13C NMR spectra. The spectral data of related
compounds were taken into account during analysis of the spectra [62-64].
The proposed structure was confirmed unambiguously by X-ray structural analysis of compound 4
(Fig. 1). The symmetrically independent part of the unit cell contains half of the molecule of compound 4,
which is at a special position at the center of symmetry and has the ap-sp-sp conformation (according to the
system of notation [68, 66] based on the geometry of the central C−N=N−C fragment, which can be either anti-
or syn-peri-planar, ap or sp respectively, and also on the orientation of the C=N bonds of the furazan ring in
relation to the central N=N fragment). It should be noted that the overwhelming majority of the azofurazans
studied by X-ray structural analysis are characterized in the crystal by the ap-ap-ap conformation [54, 69]. In
the case of compound 4, however, such conformation is sterically unfavorable on account of the repulsion
between the hydrogen atoms of the adamantane and the azo bridge.
Fig. 1. A general view of the molecule of compound 4 with the atoms represented by thermal vibration
ellipsoids of 50% probability.
The geometry of compound 4 is described well in terms of the effect of the donor and acceptor groups
on the furazan ring [67]. The N−O bonds of the furazan ring at the azo group are shorter than at the adamantane
substituent, while the lengths of the N(3)−C(12) and N(3)−N(3A) bonds (Table 2) indicate conjugation between
the furazan ring and the azo bridge. (The average length of the C−N and N=N bonds is 1.431 and 1.222 Å,
respectively [70].) Similar relationships were found earlier for the compounds presented in Table 2.
1361

1362

1363

TABLE 2. Some Bond Lengths (Å) in the Molecules of Compound 4
and Other Azofurazans
N(3)
N(3A)
N
N
R
R
C(2)
C(1)
N
N
N(1) N
N
N(2)
O
O
O(1)
R
O(1)–N(1)
1.399(10)
O(1)–N(2)
1.374(10)
N(3)–C(2)
1.413(11)
N(3)–N(3A)
–Ad (4)
1.254(14)
1.266(3)
1.255(2)
1.244(2)
–NH2 [65]
1.406(2)
1.411(2)
1.394(2)
1.355(2)
1.356(2)
1.360(2)
1.399(3)
1.400(2)
1.404(2)
–NHNO2 [54]
–OMe [66]
O
CN
[67]
1.390(3)
1.370(3)
1.410(4)
1.248(3)
N
N
O
Thus, it was shown that electrophilic reagents can be used for modification of the adamantylfurazans
skeleton of the molecule. Despite the fact that the furazan ring reduces the reactivity of the adamantane
fragment of the molecule these reactions make it possible to obtain compounds that are unavailable by other
methods. The rich possibilities of the chemistry of bromo-, nitroxy-, and hydroxyadamantanes make it possible
to hope that the obtained compounds will be effective in targeted syntheses.
EXPERIMENTAL
1
The IR spectra were recorded in KBr on a Bruker Alpha-T spectrometer. The H, 13C, and 14N NMR
spectra at the natural contents of the isomers were recorded on a Bruker AM-300 spectrometer (300, 75, and 30
MHz, respectively) in DMSO-d6 (compounds 7, 11) or in CDCl3 (the other compounds). The chemical shifts in
the 14N NMR spectra were determined with reference to MeNO2 as external standard. The two-dimensional
spectra were recorded on a Bruker Avance 600 spectrometer by the standard Bruker procedure. The mass
spectra were recorded on a Varian MAT-311A instrument, EI (70 eV). Elemental analysis was conducted on a
CHNS/O Analyser 2400 (Perkin-Elmer Instruments Series II). The melting points were determined on
Gallenkamp melting point apparatus and were not corrected. The reactions and the purity of the products were
monitored by TLC on Sorbfil plates with a fixed layer, and silica gel SiO2 40/100 was used for preparative
chromatography. The starting 3-(1-adamantyl)-4-aminofurazan (1) was obtained by the published method [26].
3-(1-Adamantyl)-4-nitrofurazan (2) and 4,4'-Di(1-adamantyl)azoxyfurazan (3). 85% H2O2 (2 ml,
2.33 g, 58.2 mmol) was added dropwise to a mixture of CH2Cl2 (40 ml) and trifluoroacetic anhydride (14 ml,
21.00 g, 0.10 mol) cooled to 8°C. Amine 1 (2.00 g, 9.12 mmol) was then added to the obtained solution
portionwise with stirring so that the temperature did not exceed 15°C. The reaction mixture was stirred at 15°C
for 2 h and was then refluxed for 1 h. After cooling, H2O (50 ml) was added. The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (2×15 ml). The combined extracts were washed with water
(3×20 ml) and dried over MgSO4. The solvent was removed at reduced pressure, and the remaining oil was
separated by column chromatography with gradient elution with hexane → 1:1 hexane–CHCl3.
The first fraction (Rf 0.71, hexane–CHCl3, 1:1) was compound 2. Yield 0.73 g (32%), light-yellow oil,
nD24 1.513. Found, %: C 57.91; H 6.12; N 16.78. C12H15N3O3. Calculated, %: C 57.82; H 6.07; N 16.86.
1364

The second fraction (Rf 0.27, hexane–CHCl3, 1:1) was compound 3. Yield 0.14 g (7%), fine colorless
crystals, mp 211-212°C (hexane). Found, %: C 64.06; H 6.79; N 18.79. C24H30N6O3. Calculated, %: C 63.98;
H 6.71; N 18.65.
4,4'-Di(1-adamantyl)azofurazan (4). Conc. HCl (6 ml) was added to a solution of the amine 1 (0.50 g,
2.28 mmol) in CCl4 (12 ml). A solution of KMnO4 (0.54 g, 3.42 mmol) in H2O (30 ml) was added to the
obtained two-phase mixture with vigorous stirring. The reaction mixture was then stirred for a further 2 h at
room temperature and diluted with CCl4 (30 ml). Oxalic acid was then added in portions until the reaction
mixture was colorless. The organic layer was separated, washed with water (3×20 ml), and dried over MgSO4,
and the obtained solution was passed through a thin layer of silica gel on a Schott filter. The solvent was
removed at reduced pressure, and the residue was recrystallized from CHCl3. Yield 0.40 g (81%), orange
crystals, mp 263-264°C. Found, %: C 66.39; H 7.03; N 19.23. C24H30N6O2. Calculated, %: C 66.34; H 6.96;
N 19.34.
Oxidative Bromination of Amine 1. KBr (0.238 g, 2 mmol) and NaNO3 (0.170 g, 2 mmol) were added
to a solution of the amine 1 (0.440 g, 2 mmol) in trifluoroacetic acid (6 ml). The mixture was stirred at room
temperature for 3 days and was then poured into H2O (20 ml). The precipitate was filtered off and dried. The
obtained mixture was separated on a column, gradient elution with hexane–CHCl3, 5:1 → CHCl3 → Et2O.
The first fraction (Rf 0.63, hexane–CHCl3, 5:1) was 2-(1-adamantyl)-2-bromo-2-nitroacetonitrile (5).
Yield 0.09 g (15%), colorless crystals, mp 99-100°C (CCl4). IR spectrum, ν, cm-1: 3449, 2935, 2914, 2855,
1
1572, 1447, 1332, 1304, 1189, 1090, 1055, 976, 869, 849, 824, 773, 754. H NMR spectrum, δ, ppm (J, Hz):
2.17 (3H, s, 3',5',7'-CH); 1.77 (6H, s, 2',8',9'-CH2); 1.69 (6H, s, 4',6',10'-CH2). 13C NMR spectrum, δ, ppm:
111.8; 91.8; 42.8; 37.2; 35.6; 28.0. 14N NMR spectrum, δ, ppm: -18.8. Mass spectrum, m/z (for 79Br isotope):
298 [M]+, 252 [M-NO2]+, 172 [M-NO2-Br]+, 144. Found, %: C 48.27; H 5.09; N 9.25. C12H15BrN2O2 (299.17).
Calculated, %: C 48.18; H 5.05; N 9.36.
The second fraction (Rf 0.49, hexane–CHCl3, 5:1) was adamantane-1-carbonitrile (6). Yield 0.035 g
(11%), colorless crystals, mp 194-195°C (mp 193-194°C [71]). The substance corresponded fully to an
authentic sample.
The third fraction (Rf 0.05, hexane–CHCl3, 1:1) was 2-(1-adamantyl)-2-hydroxyiminoacetonitrile (7).
Yield 0.073 g (18%), colorless amorphous substance, mp 143-144°C (mp 142-143°C [72]). The substance
corresponded fully to an authentic sample. 1H NMR spectrum, δ, ppm (J, Hz): 12.92 (1H, s, NOH); 2.02 (3H, s,
3',5',7'-CH); 1.77 (6H, s, 2',8',9'-CH2); 1.69 (6H, s, 4',6',10'-CH2). 13C NMR spectrum, δ, ppm: 144.8; 114.8;
44.3; 42.0; 40.7; 32.3.
The fourth fraction (Rf 0.30, EtO2) was adamantane-1-carboxylic acid (8). Yield 0.05 g (14%),
colorless amorphous substance, mp 183-184°C (mp 181-183°C [73]). The substance corresponded fully to an
authentic sample.
Bromination of Nitrofurazan 2. A catalytic amount of anhydrous AlCl3 was added to a solution of
nitrofurazan 2 (0.40 g, 1.60 mmol) in Br2 (3.4 ml, 10.5 g, 66.0 mmol) with stirring, and the mixture was
refluxed for 2 h. It was then left overnight at room temperature. The bromine was distilled, and the residue was
dissolved in CHCl2 (30 ml). The obtained solution was washed with H2O (2×10 ml) and dried over MgSO4. The
oily residue after distillation of the solvent (0.85 g) was chromatographed on a column, gradient elution with
hexane → hexane–CHCl3, 10:1 → hexane–CHCl3, 5:1 → CHCl3.
The first fraction (Rf 0.53, hexane–CHCl3, 5:1) was 1,3-dibromoadamantane (10). Yield 0.089 g
(19%), colorless plates, mp 99-101°C (mp 100-103°C [74]). Mass spectrum, m/z: 293 [M]+. The substance
corresponded fully to an authentic sample.
The second fraction (Rf 0.36, hexane–CHCl3, 5:1) was 3-(3-bromoadamantan-1-yl)-4-nitrofurazan
(9). Yield 0.325 g (62%), colorless powder, mp 68-69°C. Found, %: C 43.99; H 4.34; N 12.72. Calculated, %:
C 43.92; H 4.30; N 12.80.
3-(1-Adamantyl)-4-(nitramino)furazan (11). Amine 1 (0.200 g, 0.91 mmol) was added with vigorous
stirring to fuming nitric acid (0.3 ml, 0.450 g, 7.20 mmol) (d 1.5 g/cm3) cooled to 0°C. The reaction mixture was
1365

maintained at 0-5°C for 20 min and was then allowed to heat to room temperature. The mixture was diluted with
CF3COOH (2 ml), and the precipitate was filtered off and dried over KOH in a vacuum desiccator. Yield
0.187 g (78%), colorless powder, mp 103°C (decomp.). Found, %: C 54.65; H 6.16; N 21.13. C12H16N4O3.
Calculated, %: C 54.54; H 6.10; N 21.20.
3-(3-Nitroxyadamantan-1-yl)-4-nitrofurazan (12) and 3-(3-hydroxyadamantan-1-yl)-4-nitro-
furazan (13). Nitrofurazan 2 (0.35 g, 1.4 mmol) was added to fuming nitric acid (2.35 ml, 3.53 g, 56 mmol)
(d 1.5 g/cm3). The obtained solution was stirred at room temperature for 1.0 h. The reaction mixture was then
heated to 40°C, maintained at this temperature for 1.5 h, cooled to 15°C, and poured onto ice (30 g). The
product was extracted with CH2Cl2 (4×20 ml), and the combined extracts were dried over MgSO4 and
evaporated. The residue (0.27 g) was separated on a column, gradient elution with CCl4 → CH2Cl2–CCl4, 1:1 →
CH2Cl2.
24
The first fraction (Rf 0.25, CCl4) was compound 12. Yield 0.240 g (55%), yellowish oil, nD 1.536.
Found, %: C 46.53; H 4.64; N 18.00. C12H14N4O6. Calculated, %: C 46.45; H 4.55; N 18.06.
The second fraction (Rf 0.02, CCl4) was compound 13. Yield 0.067 g (18%), colorless amorphous
substance, mp 82-83°C. Found, %: C 54.44; H 5.75; N 15.77. C12H15N3O4. Calculated, %: C 54.33; H 5.70;
N 15.84
X-ray Crystallographic Analysis of Compound 4. The orange crystals of compound 4 (C24H30N6O2,
М 434.55) at 100 K are monoclinic: a 10.9952(8), b 6.5924(5), c 28.939(2) Å;  99.6260(10)°; V 2068.1(3) Å3;
Z 8; space group C2/с;  0.092 mm-1; dcalc 1.396 g/cm3. The intensities of 15690 reflections were determined on
a SMART APEX2 CCD diffractometer (λ(MoKα) 0.71073 Å, graphite monochromator, ω-scan, 2θ < 66°). The
initial set of measured intensities was processed by the SAINT and SADABS software included in the APEX2
package [75]. The structure was solved by the direct method and refined by full-matrix least-squares treatment
in anisotropic approximation for the non-hydrogen atoms in F2hkl. The positions of the hydrogen atoms were
calculated geometrically and refined in the "rider" model. During refinement, 3876 independent reflections were
used (Rint 0.0278). The probability of the refinement in all the unique reflections was wR2 0.0181 (R1 0.0391 in
3306 reflections with I > 2σ(I)). All the calculations were done with SHELXTL software [76]. The structure
was deposited at the Cambridge Crystallographic Data Center (deposit CCDC 949778).
Individual parts of the work were carried out with support from the Department of Chemistry and
Materials Science, Russian Academy of Sciences (program OKhNM-04) and also from the Russian Foundation
for Basic Research (project No. 12-03-12012 OFI-M). The authors express their gratitude to Prof.
A. S. Shashkov for recording and discussing the two-dimensional NMR spectra.
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