A novel regioselective method for aminostilbene preparation - The role of sodium azide

Article abstract of DOI:10.1016/j.tetlet.2012.09.066

The reaction between a derivative of 2,4-dinitrostilbene and sodium azide gave consistently 2-amino-4-nitrostilbenes as the sole products instead of the expected azidonitrostilbene. Based on this finding, we present a one-step preparative method for selec

Full text of DOI:10.1016/j.tetlet.2012.09.066

Tetrahedron Letters 53 (2012) 6504–6507
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel regioselective method for aminostilbene preparation—the role
of sodium azide
⇑
Katarzyna Janowska, Rafał Matczak, Jacek Zakrzewski, Hanna Krawczyk
Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 May 2012
Revised 31 August 2012
Accepted 17 September 2012
Available online 23 September 2012
The reaction between a derivative of 2,4-dinitrostilbene and sodium azide gave consistently 2-amino-4-
nitrostilbenes as the sole products instead of the expected azidonitrostilbene. Based on this finding, we
present a one-step preparative method for selective transformation of the ortho-NO2 group in (E)-2,4-
dinitrostilbenes into an ortho-NH2 group to give (E)-2-amino-4-nitrostilbenes.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Selective amination
Azides
Stilbenes
The chemistry and photochemistry of stilbenes have been
investigated extensively.1–3 Stilbene derivatives are usually ther-
mally and chemically stable and possess absorption and fluores-
cence properties that can easily be monitored by relevant optical
techniques. They play an increasingly prominent role in the area
of photophysical, photochemical, biophysical and biomedical
investigations. Preclinical research on cells, organs and animals
using stilbenes has attracted significant attention as a necessary
step for further clinical investigation and the invention of new
drugs. Data on anticancer and other chemopreventive activities
of resveratrol [RES, (E)-3,5,40-trihydroxystilbene] and other stilb-
enes with a methoxy, nitro or amine group have been summa-
rized.4 Stilbene derivatives such as CA1 and the corresponding
nitrogen analogue, AVE8062, along with the diphenol phosphate
prodrug CA1P (also known as Oxi4503), CA4P (Fig. 1) and the cor-
responding nitrogen analogue, belong to the group of vascular-dis-
rupting agents (VDAs) which have been subjected to clinical trials
in humans.5–11
Due to the widespread use and importance of stilbenes, new,
more selective and rapid methods for their synthesis are required.
In continuation of our studies on stilbenes, we found, to our sur-
prise, that the reaction between a derivative of 2,4-dinitrostilbene
1–5 and sodium azide always gave the corresponding 2-amino-4-
nitrostilbene 6–10 as the sole product instead of the expected azi-
donitrostilbene12 (Scheme 1). The conversion of a nitro group into
an amine usually proceeds in the presence of a metal (Sn, Zn) and
acids, but when using sodium azide, the product of substitution is
obtained. Several reactions of azides in which the desired prod-
ucts13–16 were not obtained, have been reported. In the first case,
Sajiki and co-workers13 reported that the cross-coupling reaction
between ethyl 4-bromobenzoate and trimethylsilyl azide in the
presence of Cu(I) catalysts and triphenylphosphine gave ethyl 4-
aminobenzoate as the product instead of the expected ethyl 4-azi-
dobenzoate. Two further articles describing copper-mediated
aminations of aryl halides utilizing azides as the amine source have
appeared.14,15 However, the mechanism of the redox process was
16
ˇ
not disclosed. Kolarovic et al. hypothesized that the strongly
electron-withdrawing nitro group (with 1-iodo-4-nitrobenzene as
the substrate in the reaction) made 1-azido-4-nitrobenzene
(formed in situ) prone to reduction, and that water served as a
hydrogen donor for the transformation into 4-nitroaniline.
Optimization of our reaction conditions for this unexpected
transformation revealed the following: (1) sodium azide was re-
quired as without this reagent no product was observed, (2)
120 °C and DMF or DMSO was the best combination of tempera-
ture and solvent, (3) the reaction proceeded in air or under an ar-
gon atmosphere. The reaction was regiospecific with only the
ortho-NO2 group replaced. We obtained two known (6 and 7)17,18
and three new (8–10) stilbenes using this method (Table 1).
We undertook experiments to investigate the mechanism of
this reaction. Shevelev and co-workers12 demonstrated that the
ortho-NO2 group in (E)-2,4,6-trinitrostilbenes was replaced regio-
selectively when exposed to an azide such as NaN3 at ambient
temperature.
We hypothesized initially that in compounds 1–5 the ortho-NO2
group might also be replaced in the reaction with NaN3. Unfortu-
nately, despite running the reaction for 13 h at ambient tempera-
ture, the expected product was not observed. After increasing the
temperature to 120 °C, we obtained products 6–10. Complete 1H
⇑
Corresponding author. Fax: +48 22 628 27 41.
E-mail address: hkraw@ch.pw.edu.pl (H. Krawczyk).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.066

K. Janowska et al. / Tetrahedron Letters 53 (2012) 6504–6507
6505
Table 1
H3CO
H3CO
Optimization of the reaction conditions for the transformation of 2,4-dinitrostilbene
derivatives 1–5 into products 6–10
Entry
Substrate
Product
Time (h)
Yielda,b (%)
1
2
3
4
5
1
2
3
4
5
6
7
8
9
8
85
80
85
89
75
15
20
20
20
OCH3
OPO(OH)2
OCH3
10
a
Isolated yield.
DMF was used as the solvent; temperature = 120 °C.
CA4P
b
Figure 1. The structure of CA4P.
reaction solution. Moreover, when the experiment was conducted
in dry DMSO the products were still present, but in lower yields.
These experiments indicate that water probably serves as the
hydrogen donor in these processes. Furthermore, it is also not clear
why only the nitro group at position 2 undergoes this transforma-
tion. It is known19 that the nitro groups in 2-methyl-1,3,5-trinitro-
benzene (TNT) are non-equivalent. Thus, the para-nitro group is
coplanar with the benzene ring, whereas the two ortho-nitro
groups are rotated around the C–N axis by ꢀ40o and ꢀ20o with re-
spect to the benzene ring, due to the steric effect of the methyl
group. This substantial non-coplanarity of the nitro group favours,
in the case of the ortho-nitro group in TNT, the necessary change in
hybridization of the ipso-C atom from sp2 to sp3 upon formation of
and 13C NMR spectroscopic data of all the products are shown in
Tables 2 and 3 (see Supplementary data). The 1H and 13C NMR res-
onances were assigned unequivocally based on the combined
information from 1D to 2D NMR (gCOSY, gHSQC and gHMBC)
experiments. Coupling constants (1H–1H) were measured directly
from resolution-enhanced 1D spectra and confirmed, when neces-
sary, by homo-decoupling. gHSQC and gHMBC analysis allowed the
assignment of the stilbene regiochemistry (Fig. 2), determination
of the H-3, H-5, H-6 resonances and the assignment of important
correlations (all of which occurred in all the stilbenes). The follow-
ing correlations were observed for product 8: protons of the amine
group (4.09 ppm) with C-1 (129.47 ppm) and C-3 (110.50 ppm); C-
the ipso-r-complex, because rotation of the nitro group decreases
2 (144.50 ppm) with H-3 (7.56 ppm), H
(7.49 ppm); H-3 (7.56 ppm) with C-1 (129.47 ppm), C-2
(144.50 ppm), C-4 (147.89 ppm) and C-5 (113.91 ppm).
a 7.07 ppm and H-6
its degree of conjugation with the aromatic ring. In order to study
the positioning of the nitro groups, the optimum structure of 2
using the DFT B3LYP/6-311++G(2d,p) method was calculated. It ap-
peared that as in TNT the ortho-nitro group of 2 was rotated around
the C–N axis by ꢀ32.5o and ꢀ32.8o, and that the para-nitro group
was coplanar with respect to the benzene ring. We hypothesize
that the strong electron-withdrawing nitro group at position 4 in
compounds 1–5 makes the nitro group at position 2 prone to sub-
stitution by the azide group and, as a result, vulnerable to
reduction.
In conclusion, we have demonstrated that sodium azide re-
acts regiospecifically with only one of the two nitro groups
among a variety of dinitrostilbenes, without the need for a cat-
alyst, in DMF or DMSO at 120 °C to give 2-amino-4-nitrostilb-
enes as the sole products in satisfactory yields. This process
can be regarded as a one-step preparative method for selective
transformation of the ortho-NO2 group in (E)-2,4-dinitrostilbenes
into an ortho-NH2 group to give (E)-2-amino-4-nitrostilbenes. On
the basis of our investigations, we hypothesize that the strongly
Only in the case of substrate 2 did we observe the intermediate
azide product 7a (Fig. 3), which after about 1 h gradually disap-
peared with simultaneous formation of the final product 7. NMR,
IR and MS analysis of this intermediate showed the presence of
an azide group at position 2 (see Tables 2 and 3 in the Supplemen-
tary data). However, we still did not know what the source of the
hydrogen was for the transformation of the nitro compounds into
2-amino-4-nitrostilbenes in these reactions. We observed a signal
that originated from the hydrogen of the amine group in the 1H
NMR spectrum. Having investigated the source of the hydrogen do-
nor, we examined the reaction of 6 in DMSO-d6. In the proton spec-
trum, we did not observe the hydrogens of the amine group.
However, the 2H NMR analysis displayed the deuterium in the
amine group. Moreover pure azidostilbene 7a was heated at
120 °C for 12 h in DMF (without using NaN3) to afford product 7.
Thus, we concluded that the source of the hydrogen was in the
R
R
DMF or DMSO
120 °C, 20 h
+
NaN3
O2N
NO2
O2N
NH2
1-5
6-10
1,6: R=
2,7:
R=
OCH3
Cl
3,8: R=
4,9: R=
NO2
5,10:
R=
Scheme 1. The unanticipated formation of aminostilbenes 6–10 from nitrostilbenes 1–5 under azidation conditions.

6506
K. Janowska et al. / Tetrahedron Letters 53 (2012) 6504–6507
(a)
5'
Cl
4'
6'
H3-C3
α
6
3
1
5
3'
1'
β
2'
4
2
O2N
NH2
H5-C5
Hα-Cα
Hβ-Cβ
H6-C6
H3'-C3’
H5'-C5’
H2'-C2’
H6'-C6’
(b)
CDCl3
C3
C6
C5
Cα
C2’,C6’
C3’, C5’
C1
Cβ
C4’
C1’
C2
C4
Figure 2. g-HSQC (a) and gHMBC (b) spectra of product 8. The signals due to CDCl3 at 77.0 ppm (13C) and 7.26 ppm (1H) were used as internal reference standards.
electron-withdrawing nitro group at position 4 in the substrates
makes the nitro group at position 2 more prone to substitution
by the azide group and subsequently to reduction into an amine
group.
(25 mL) fitted with a condenser. The mixture was stirred at
120 °C for 20 h and concentrated in vacuo. The residue was purified
by flash column chromatography on silica gel (toluene ? toluene:
MeOH, 4:1).
Acknowledgment
General procedure for the reductive amination of
dinitrostilbenes with NaN3 (Table 1)
This work was supported by the Faculty of Chemistry, Warsaw
University of Technology, and Ministry of Science and Higher
Education.
2,4-Dinitrostilbene (1.70 mmol), and NaN3 (190 mg, 2.95 mmol)
in DMF (15 ml), were sequentially added to a three-necked flask

K. Janowska et al. / Tetrahedron Letters 53 (2012) 6504–6507
3. Grabowski, R.; Rotkiewicz, W.; Rettig, W. Chem. Rev. 2003, 103, 3899.
6507
OCH3
4. For reviews, see: Likhtenshtein, G. Stilbenes, Applications in Chemistry, Life
Sciences and Materials Science; Wiley-VCH: Weinheim, 2010; Siles, R.; Ackley, J.
F.; Hadimani, M. B.; Hall, J. J.; Mugabe, B. E.; Guddneppanavar, R.; Monk, K. A.;
Chapuis, J.-Ch.; Pettit, G. R.; Chaplin, D. J.; Edvardsen, K.; Trawick, M. L.; Garner,
Ch. M.; Pinney, K. G. J. Nat. Prod. 2008, 71, 313.
5. Young, S.; Chaplin, D. J. Expert Opin. Investig. Drugs 2004, 13, 1171.
6. Demers, B.; Vrignaud, P.; Bissery, M. J. Clin. Oncol. (2006 ASCO Annual Meeting
Proceedings, Part 1) 2006, 24, 13074 (abstract).
O2N
N3
7. Hori, K.; Saito, S. Br. J. Cancer 2003, 89, 1334.
8. Akerley, W. L.; Schabel, M.; Morrell, G.; Horvath, E.; Yu, M.; Johnsson, B.;
Arbogast, K. J. Clin. Oncol. (2007 ASCO Annual Meeting Proceedings, Part 1) 2007,
25, 14060 (abstract).
9. Patterson, D. M.; Ross, P.; Koetz, B.; Saleem, A.; Stratford, M.; Stirling, J.;
Padhani, A.; Asselin, M.; Price, P.; Rustin, G. J. J. Clin. Oncol. (2007 ASCO Annual
Meeting Proceedings, Part 1) 2007, 25, 14146 (abstract).
7a
Figure 3. The structure of 7a.
10. Rice, L.; Pampo, Ch.; Lepler, S.; Rojiani, A. M.; Siemann, D. W. Microvasc. Res.
2011, 81, 44.
11. Subbiah, I. M.; Lenihan, D. J.; Tsimberidou, A. M. Oncologist 2011, 16, 1120.
12. Sapozhnikov, O. Yu.; Dyachuk, V. V.; Dutov, M. D.; Kachala, V. V.; Shevelev, S. A.
Russ. Chem. Bull., Int. Ed. 2005, 54, 1331.
13. Monguchi, Y.; Maejima, T.; Mori, S.; Maegawa, T.; Sajiki, H. Chem. Eur. J. 2010,
16, 7372.
14. Zhao, H.; Fu, H.; Qiao, R. J. Org. Chem. 2010, 75, 3311.
15. Markiewicz, J. T.; Wiest, O.; Helquist, P. J. Org. Chem. 2010, 75, 4887.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
09.066.
ˇ
16. Kolarovic, A.; Schnürch, M.; Mihovilovic, M. D. J. Org. Chem. 2011, 76, 2613.
References and notes
17. McGookin, A. J. Soc. Chem. Ind. 1949, 68, 195.
18. Kim, J. S.; Sun, Q.; Gatto, B.; Yu, Ch.; Liu, A.; Leroy, F. L.; La Voie, E. J. Bioorg. Med.
Chem. 1996, 4, 621.
1. Ververidis, F.; Trantas, E.; Douglas, C.; Vollmer, G.; Kretzschmar, G.;
Panopoulos, N. Biotechnol. J. 2007, 2, 1214.
2. Momotake, A.; Arai, T. J. Photochem. Photobiol., C 2004, 5, 1.
19. Barnes, J.; Golnazarians, W. Acta. Crystallogr. 1987, 43C, 549.