Unusual reaction of 4-nitrobenzofurazan with amines

Article abstract of DOI:10.1016/j.mencom.2008.11.015

The treatment of 4-nitrobenzofurazan with secondary amines resulted in the formation of 4-amino-5,7-bis(dialkylamino)-benzofurazans, as established by X-ray diffraction analyses; this is the first example of S_N^H reaction with synchro

Full text of DOI:10.1016/j.mencom.2008.11.015

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 329–331
Unusual reaction of 4-nitrobenzofurazan with amines
Feliks S. Levinson,*a Roman V. Varganov,a Marsel M. Zakiev,a Ilmira M. Shakirova,a
Aleksei B. Sheremetev,*b Dmitry E. Dmitriev,b Dmitry B. Krivolapov,c Igor A. Litvinov,c
Dilyara R. Sharafutdinovac and Yurii Ya. Efremovc
a Kazan State Technological University, 420015 Kazan, Russian Federation
b N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: sab@ioc.ac.ru
c A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Centre of the Russian Academy of
Sciences, 420088 Kazan, Russian Federation
DOI: 10.1016/j.mencom.2008.11.015
The treatment of 4-nitrobenzofurazan with secondary amines resulted in the formation of 4-amino-5,7-bis(dialkylamino)-
benzofurazans, as established by X-ray diffraction analyses; this is the first example of SHN reaction with synchronous alteration of
three functions.
Nucleophilic (hetero)aromatic substitution of hydrogen (SHN)
is a powerful tool in organic synthesis.1 In most cases, this
process is especially effective for selective C–C, C–N, C–O and
C–S bond formation, and many nitro(het)arenes and activated
heterocycles have been functionalized by the SHN technique.
This process consists of the addition of a nucleophile to
nitroarenes followed by oxidative aromatization of the initially
formed anionic σ-complex (Scheme 1). The ease of the oxida-
tion was found to depend inversely on the electron deficiency
of the parent molecule.1,2 For example, adducts from 4-nitro-
benzofuroxan were more easily oxidized than those from
4,6-dinitrobenzofuroxan. However, the oxidative pathway is not
clear, it may be that the solvent, air, or the starting molecule
itself plays an active role in the oxidation process.
to undergo smooth SHN reactions to secondary amines, with
simultaneous reduction of the nitro group to the amino group.
When compound 1 was treated at room temperature with a
deficiency of morpholine (1 mol) in DMF for 0.5 h, a complex
reaction ensued, in which starting 1 and four new compounds
were fixed by TLC. The same four products were observed
when the nitrobenzofurazan 1 was treated with morpholine
(4 mol) in dioxane for 1 h. With more morpholine (5 mol) at
room temperature for 48 h, the reaction was less complex and two
products were isolated by careful chromatography (Scheme 2).
The first product (11%) was identified as 4-nitro-7-morpholino-
benzofurazan 2a.† The second major (48%) product 3a was
found to have a molecular formula of C14H19N5O3, suggesting
that two morpholine moieties have been incorporated and that
the new product has arisen via the nitro group reduction.† Mass
spectral analysis of the product gave a parent ion at m/z 305,
consistent with molecular formula specified above. In addition,
mass spectrum shows significant peaks due to loss of a NO
moiety (m/z 275) from the molecular ion and then of a morpholine
group (m/z 188) as might be expected from the benzofurazan
In contrast to classical nucleophilic aromatic substitution
(SiNpsoAr), usually accompanied by HHal, HNO2 or RSO3H
elimination, at SHN reactions a water molecule is typically released,
that is fascinating to create environmentally friendly processes.
Nitrobenzofuroxans have received much attention3 since
the neutral 10-π-electron-deficient heteroaromatic compounds
exhibited an extremely high electrophilic character2(b),4 relative
to many covalent nucleophilic addition and substitution processes.
Surprisingly, only a few publications have reported on the SHN
reaction of benzofurazan derivatives. Thus, anthra[1,2-c]furazan-
6,11-dione5,6(a) and anthra[2,3-c]furazan-5,10-dione6(b) readily
reacted with sulfite ions,5 ammonia, primary and secondary
amines6 giving corresponding 4-substituted derivatives; 4-nitro-
benzofurazan 1 underwent facile competitive monoaddition of
anionic nucleophiles (MeO–,7(a) mononitroalkane anions,2(b),7(b),(c)
sulfite ions7(d)) to the 5- or 7-positions under experimental con-
ditions. All reactions led to relatively stable intermediated anionic
σ-adducts.
†
All spectroscopic and analytical data were consistent with the structures
assigned. The identity of products 2a–d was confirmed by NMR spectra,
elemental analysis, melting points, HRMS and comparison with the
published data.
For 2a: mp 227–228 °C (lit.,10(a) 225–226 °C).
For 2b: mp 170–171 °C (lit.,10(a) 169–170 °C).
For 2c: mp 116–117 °C (lit.,10(b) 115–116 °C).
For 2d: mp 210–211 °C (lit.,10(c) 210 °C).
For 3a: mp 204–205 °C. 1H NMR ([2H6]DMSO) d: 2.82 (m, 4H), 3.23
(m, 4H), 3.79 (m, 8H), 5.15 (br. s, 2H, NH2), 6.52 (s, 1H). 13C NMR
([2H6]DMSO) d: 50.1, 50.2 (CH2–N), 65.9, 66.5 (CH2–O), 109.3 (C4),
120.9 (C6), 129.5 (C3), 131.3 (C5), 144.1 (C2), 145.8 (C1). MS, m/z (%):
305 [M]+ (100). Found (%): C, 55.14; N, 22.91; H, 6.30. Calc. for
C14H19N5O3 (305.34) (%): C, 55.07; N, 22.94; H, 6.27.
To expand the usefulness of benzofurazan chemistry,8 as well
as to provide a predicting tool, we undertook a study of this SHN
reaction. We found that 4-nitrobenzofurazan 1 can be induced
For 3b: mp 136–137 °C. 1H NMR ([2H6]DMSO) d: 1.38 (m, 12H), 2.66
(m, 4H), 3.61 (m, 8H), 4.37 (br. s, 2H, NH2), 6.46 (s, 1H). 13C NMR
([2H6]DMSO) d: 23.3, 23.4, 24.8, 25.7 (CH2–C), 50.4, 50.9 (CH2–N),
108.8 (C4), 119.2 (C6), 130.6 (C3), 133.2 (C5), 144.1 (C2), 145.5 (C1).
MS, m/z (%): 301 [M]+ (100). Found (%): C, 63.83; N, 23.13; H, 7.72.
Calc. for C16H23N5O (301.39) (%): C, 63.76; N, 23.24; H, 7.69.
For 3c: mp 158–160 °C, MS, m/z (%): 329 [M]+ (100), 314 [M – Me]+
(20), 313 [M – NH2]+ (17), 299 [M – NO]+ (10), 284 [M – Me – NO]+ (10).
Found (%): C, 65.71; N, 21.19; H, 8.30. Calc. for C18H27N5O (329.45)
(%): C, 65.62; N, 21.26; H, 8.26.
EWG
EWG
EWG
Nu–
– H–
H
Nu
Nu
EWG = electron-withdrawing group
Scheme 1
– 329 –
© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 329–331
H
O
C(14)
O(19)
C(20)
O
C(18)
O
O(13)
C(12)
N
N
C(17)
N(16)
C(15)
H
R2N
N
N
N
N
HNR2
A
N(10)
C(4)
C(21)
1
R2N
O
O
– H2O
C(5)
C(11)
C(6)
C(7)
4
5
HNR2
O
B
C(9)
HNR2
OH
C(8)
N(22)
N(3)
OH
N
H
OH
N
N
N
N(1)
O(2)
R2N
R2N
N
N
Figure 1 Molecular structure of 3a.
O
O
O
N
N
N
1
structure. H NMR analysis clearly indicated the presence of
the amino group and two morpholine fragments. In order to
characterize the product unambiguously, a single crystal X-ray
determination was carried out (Figure 1).‡ The molecular
dimensions of the benzofurazan unit of 3a fall within the ranges
of other benzofurazans that have been examined by X-ray
crystallography.8(b),9
NR2
R2N
H
R2N H
8
7
6
– H2O
O
2
3
N
N
N
We found that the reaction of nitrobenzofurazan 1 with other
secondary amines (Scheme 2) in dioxane at 20 °C behaves
similarly, producing corresponding disubstituted aminobenzo-
furazans 3b,c (35–50%) along with nitro products 2b,c (12–15%).
A related reaction occurred using pyrrolidine resulting, however,
in the formation of a complex mixture, from which desired
amine 3d was isolated in low yield (8%).
O
2 + 3
NR2
9
Scheme 3
The formation of amine 3 can be best rationalized through
σ-complex formation. As depicted in Scheme 3, two possibilities
can be envisaged, pathways A and B. Both pathways differ only
in position of the first amine molecule addition. These pathways,
nevertheless, afford finally product 3. Aromatization of σ-com-
plexes (4, 6 and 8) can proceed via both intramolecular redox
reactions (as, for example, at transformation 4 ® 5), and inter-
molecularly (as, for example, at transformation 7 + 8 ® 2 + 3).
Nitroso§ intermediates 5 and 9 added on next amine molecule,
followed by redox transformation.
Thus, the behavior of 4-nitrobenzofurazan 1 in SHN reaction
was found to dramatically differ from that of 4-nitrobenzo-
furoxan, where the nitro group was preserved in the product
and only a nucleophile added to the substrate at 7-position.2(a),11
The reduction of the furoxan to furazan ring was also described.11(a)
NO2
NO2
NH2
6
R2N
1
N
N
N
N
N
N
HNR2
5
4
Note that special experiments showed that compound 2a did
not react with morpholine under the similar conditions, as well
as it could not be transformed into product 3a.
O
O +
O
3
2
NR2
NR2
3a–d
The participation of the nitro group in intramolecular redox
process at SHN reaction for nitrotriazolopyrimidines was described
recently;13 at this the reduction of nitro to amino group and intro-
duction of a nucleophile to basic molecule took place.
In summary, note that we have discovered the first example
of SHN reaction with synchronous alteration of three functions.
This unusual reaction is likely to be useful for multicentral
modification of benzofurazans.
1
2a–d
a NR2 =
c NR2 =
N
N
O
N
Me
d NR2 =
b NR2 =
N
Scheme 2
X-ray diffraction data. Compound 3a, C14H19N5O3, M = 305.34, mono-
References
1 (a) O. N. Chupakhin and I. Ya. Postovskii, Usp. Khim., 1976, 45, 908
(Russ. Chem. Rev., 1976, 45, 454); (b) L. M. Epshtein, Usp. Khim., 1979,
48, 1600 (Russ. Chem. Rev., 1979, 48, 854); (c) F. Terrier, Nucleophilic
Aromatic Displacement, VCH, New York, 1991; (d) O. N. Chupakhin,
V. N. Charushin and H. C. van der Plas, Nucleophilic Aromatic Sub-
stitution of Hydrogen, New York, San Diego, Academic Press, 1994; (e)
M. Makosza, Izv. Akad. Nauk, Ser. Khim., 1996, 531 (Russ. Chem. Bull.,
1996, 45, 491); (f) D. N. Kozhevnikov, V. L. Rusinov and O. N.
Chupakhin, Usp. Khim., 1998, 67, 707 (Russ. Chem. Rev., 1998, 67, 633);
(g) O. N. Chupakhin and D. N. Beresnev, Usp. Khim., 2002, 71, 803 (Russ.
Chem. Rev., 2002, 71, 707); (h) M. Makosza and K. Wojciechowskii,
Chem. Rev., 2004, 104, 2631; (i) V. N. Charushin and O. N. Chupakhin,
Mendeleev Commun., 2007, 17, 249; (j) A. V. Gulevskaya and A. F.
Pozharskii, Adv. Heterocycl. Chem., 2007, 93, 57.
‡
clinic, space group P21/c, a = 11.216(2), b = 17.002(3) and c = 7.955(4) Å,
b = 101.69(2)°, V = 1485.5(8) Å3, Z = 4, dcalc = 1.365 g cm–3. Cell parameters
and intensities of 3008 independent reflections (1341 with I ³ 2s) were
measured on an Enraf-Nonius CAD-4 diffractometer in the w/2q-scan
mode, q £ 74.21°, using CuKα radiation with a graphite monochromator.
Data were corrected for an absorption effect [m(Mo) = 8.21 cm–1]. The
structure was solved by a direct method using the SIR14(a) program and
refined by the full matrix least-squares using the SHELXL9714(b) program.
All non-hydrogen atoms were refined anisotropically. The hydrogen atoms
were calculated and refined as riding atoms. The final residuals were
R(F02) = 0.054, Rw(F02) = 0.119. All calculations were performed on PC
using WinGX14(c) program. Cell parameters, data collection and data
reduction were performed on Alpha Station 200 computer using MoLEN14(d)
program. All figures were made using the program PLATON.14(e)
2 (a) G. Moutiers, J. Pinson, F. Terrier and R. Goumont, Chem. Eur. J.,
2001, 7, 1712; (b) R. Goumont, E. Jan, M. Makosza and F. Terrier, Org.
Biomol. Chem., 2003, 1, 2192; (c) M. R. Crampton, R. E. A. Lunn and
D. Lucas, Org. Biomol. Chem., 2003, 1, 3438.
CCDC 694600 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2008.
Recently, the possibility of nitrosobenzenes participation in SHN reaction
§
was described.12
– 330 –

Mendeleev Commun., 2008, 18, 329–331
(a) A. Gasco and A. J. Boulton, Adv. Heterocycl. Chem., 1981, 29, 251;
3
Transl.), 2003, 37, 578]; (e) F. S. Levison, S. A. Akimova, E. A.
Ermolaeva, B. I. Khairutdinov and M. I. Evgen’ev, Zh. Obshch. Khim.,
2005, 75, 988 (Russ. J. Gen. Chem., 2005, 75, 933); (f) M. I. Evgen’ev,
I. I. Evgen’eva, F. S. Levinson, E. A. Ermolaeva and Ya. R. Valitova,
Zh. Anal. Khim., 2006, 61, 143 [J. Anal. Chem. (Engl. Transl.), 2006,
61, 133].
(a) H. Suzuki, T. Kurihara, T. Kaino and F. Ebisawa, Acta Crystallogr.,
Sect. C: Cryst. Struct. Commun., 1988, 44, 484; (b) G. Ermondi,
S. Visentin, D. Boschi, R. Fruttero and A. Gasco, J. Mol. Struct., 2000,
523, 149; (c) S. Saha, Acta Crystallogr., Sect. C: Cryst. Struct. Commun.,
2002, 58, o174; (d) B. Heyne, C. Beddie and J. C. Scaiano, Org. Biomol.
Chem., 2007, 5, 1454.
(b) A. R. Katritsky and M. F. Gordeev, Heterocycles, 1993, 35, 483;
(c) R. M. Paton, in Comprehensive Heterocyclic Chemistry II, eds.
A. R. Katritsky, C. W. Rees and E. F. V. Scriven, Pergamon, 1996, vol. 4,
p. 229; (d) L. I. Khmel’nitskii, S. S. Novikov and T. I. Godovikova,
Khimiya furoksanov. Struktura i sintez (Chemistry of Furoxans. Structure
and Synthesis), 2nd edn., Nauka, Moscow, 1996 (in Russian); (e) L. I.
Khmel’nitskii, S. S. Novikov and T. I. Godovikova, Khimiya furoksanov.
Reaktsii i primenenie (Chemistry of Furoxans. Reactions and Applica-
tions), 2nd edn., Nauka, Moscow, 1996 (in Russian); (f) H. Cerecetto
and M. Gonzalez, Top Heterocycl. Chem., 2007, 10, 265.
(a) F. Terrier, S. Lakhdar, T. Boubaker and R. Gounont, J. Org. Chem.,
2005, 70, 6242; (b) P. K. Chattaraj, U. Sarkar and D. R. Roy, Chem. Rev.,
2006, 106, 2065.
M. V. Gorelik, T. P. Kononova and M. S. Dokunikhin, Khim. Geterotsikl.
Soedin., 1967, 545 [Chem. Heterocycl. Compd. (Engl. Transl.), 1967, 3,
438].
9
4
5
6
10 (a) P. B. Ghosh, J. Chem. Soc. (B), 1968, 334; (b) H. Heberer, H. Kersting
and H. Matschiner, J. Prakt. Chem., 1985, 327, 487; (c) M. R. Crampton,
C. Isanbor and T. C. Willett, Can. J. Chem., 2005, 83, 1227.
11 (a) M. R. Crampton, J. Delaney and L. C. Rabbitt, J. Chem. Soc., Perkin
Trans. 2, 1999, 2473; (b) C. Boga and L. Forlani, J. Chem. Soc., Perkin
Trans. 2, 2001, 1408.
(a) M. V. Gorelik, T. P. Kononova and M. S. Dokunikhin, Khim. Geterotsikl.
Soedin., 1968, 345 [Chem. Heterocycl. Compd. (Engl. Transl.), 1968, 4,
463]; (b) M. V. Gorelik and V. I. Lomzakova, Khim. Geterotsikl. Soedin.,
1974, 1275 [Chem. Heterocycl. Compd. (Engl. Transl.), 1974, 10,
1109].
12 L. M. Gornostaev, E. A. Bocharova and N. V. Geets, Zh. Org. Khim.,
2006, 42, 1310 (Russ. J. Org. Chem., 2006, 42, 1289).
13 G. L. Rusinov, E. B. Gorbunov, V. N. Charushin and O. N. Chupakhin,
Tetrahedron Lett., 2007, 48, 5873.
7
8
(a) L. Di Nunno, S. Florio and P. E. Todesco, J. Chem. Soc., Perkin
Trans. 2, 1975, 1469; (b) B. H. M. Asghar and M. R. Crampton, Org.
Biomol. Chem., 2007, 5, 1646; (c) B. H. M. Asghar and M. R. Crampton,
J. Phys. Org. Chem., 2007, 20, 702; (d) M. R. Crampton, L. M. Pearce
and L. C. Rabbitt, J. Chem. Soc., Perkin Trans. 2, 2002, 257.
(a) M. I. Evgen’ev and F. S. Levinson, Khim. Geterotsikl. Soedin., 1991,
1565 [Chem. Heterocycl. Compd. (Engl. Transl.), 1991, 27, 1265];
(b) F. S. Levinson, S. I. Efimov, B. I. Buzykin, A. T. Gubaidullin, D. B.
Krivolapov and I. A. Litvinov, Izv. Akad. Nauk, Ser. Khim., 2002, 101
(Russ. Chem. Bull., Int. Ed., 2002, 51, 105); (c) F. S. Levinson,
M. I. Evgen’ev, E. A. Ermolaeva, S. I. Efimov, I. F. Falyakhov, T. V.
Garipov and R. G. Karimova, Khim. Farm. Zh., 2003, 37 (10), 12
[Pharm. Chem. J. (Engl. Transl.), 2003, 37, 522]; (d) F. S. Levinson,
M. I. Evgen’ev, E. A. Ermolaeva, S. I. Efimov, T. V. Garipov and R. G.
Karimova, Khim. Farm. Zh., 2003, 37 (11), 14 [Pharm. Chem. J. (Engl.
14 (a) A. Altomare, G. Cascarano, C. Giacovazzo and D. Viterbo, Acta
Crystallogr., Sect. A., 1991, 47, 744; (b) G. M. Sheldrick, SHELXS-97,
Program for Crystal Structure Solutions, University of Göttingen,
Germany, 1997; (c) L. J. Farrugia, J. Appl. Crystallogr., 1999, 32, 837;
(d) L. H. Straver and A. J. Schierbeek, MOLEN. Structure Determination
System, Nonius B.V. Delft. Netherlands, 1994, vol. 1, 2; (e) A. L. Spek,
Acta Crystallogr., Sect. A, 1990, 46, 34.
Received: 14th July 2008; Com. 08/3179
– 331 –