New sterically unhindered benzoquinonemonoimines

Article abstract of DOI:10.1016/j.tetlet.2011.05.035

We accidentally found that the F→OH conversion by direct hydroxylation of electron deficient aryls above 150 °C allows the isolation of the precursors of novel quinonemonoimines 9, previously unknown.

Full text of DOI:10.1016/j.tetlet.2011.05.035

Tetrahedron Letters 52 (2011) 3678–3680
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New sterically unhindered benzoquinonemonoimines
Mounia Touil a,b, Mohammed Lachkar b, Olivier Siri a,
⇑
a Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), UPR 3118 CNRS, Aix-Marseille Université, Campus de Luminy, Case 913, F-13288 Marseille cedex 09, France
b Université Sidi Mohamed Ben Abdellah, Faculté des Sciences Dhar El Mahraz, Laboratoire d’Ingénierie des Matériaux Organométalliques et Moléculaires ‘‘L.I.M.O.M.’’,
Département de Chimie, B.P. 1796 (Atlas), 30000 Fès, Morocco
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 December 2010
Revised 9 May 2011
Accepted 9 May 2011
Available online 15 May 2011
We accidentally found that the F?OH conversion by direct hydroxylation of electron deficient aryls
above 150 °C allows the isolation of the precursors of novel quinonemonoimines 9, previously unknown.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Quinone
Nucleophilic aromatic substitution
HO
O
O
H2N
O
NH
The synthesis of molecules exhibiting a quinoid structure con-
tinues to spur active investigations because of their implication
in many areas of chemistry and biology.1 More specifically, benzo-
quinones of type 1 are of major importance as bioinhibitors by
analogy with closely related C-substituted derivatives2–10 owing
to the presence of acidic hydrogens that might interact with the
ATP binding site through H-bonds.2 Accordingly, the access to
low molecular weight analogues is obviously a promising approach
for the development of alternative anticancer agents.2 Curiously,
quinonemonoimine analogues 2 are hitherto unknown whereas
their closely related structure should not only be very attractive
in biology—as a potential new class of bioinhibitors by analogy
with 12–10—but also in color11 and coordination12 chemistry as
acidochromes and ligands, respectively. It is noteworthy that only
N-substituted molecules of type 313,14 and 415 have been reported
in the literature for biochemistry14 or hair colorant15 applications
whereas 2—unsubstituted in the ‘upper’ part—appears much more
attractive due to the presence of additional H-donor sites and/or
possible further functionalization of the nitrogen atoms. Therefore,
the development of a versatile route that would give access to such
molecules (2) would be very useful to enlarge the scope of this
family of compounds. In the course of this study, the possible
displacement of halogens by hydroxide anion on electron poor
aromatic rings was envisaged although this transformation is
often difficult16a,b without any cationic catalyst,16c–e oxidative pro-
cesses16f or sigmatropic rearrangements.16g
NH
R
NH
R
1
2
R1
R2
N
R2
R3
N
HN
HN
NH
R1
NH2
O
O
4
3
Herein, we wish to report the synthesis of unprecedented
aminoquinonemonoimines of type 2. These molecules (8) were ob-
tained from electron deficient diaryl intermediates (7) that could
be isolated from a F?OH conversion above 150 °C.
We recently reported a straightforward synthesis of the azaca-
lix[4]arene precursor 7a by condensation of 1,3-diaminobenzene
5a with the commercially available electron deficient aryl 6 in
refluxing EtOH (Scheme 1, route i).17 When the reaction was per-
formed in wet DMSO at room temperature (rt), 7a was obtained
in 51% yield (Scheme 1, route ii). By studying this reaction in more
detail, we have now found—accidentally—that the same reaction at
160 °C affords instead the hydroxy analogue 8a in 35% yield
(Scheme 2).18
Its IR spectrum shows a strong vibration band at 1252 cmÀ1 and
its 1H NMR reveals the lack of JH–F coupling and an additional res-
onance at 10.93 ppm by comparison with 7a.
These observations are in agreement with the replacement of
the F atom in 7a (soluble in DMSO) by an OH group in 8a (Scheme
⇑
Corresponding author. Tel.: +33 617 248 134; fax: +33 491 829 580.
E-mail address: siri@univmed.fr (O. Siri).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.035

M. Touil et al. / Tetrahedron Letters 52 (2011) 3678–3680
3679
R1
O2N
F
NO2
F
R2
R3
R1
R2
R3
6
(1 equiv.)
NH
F
NO2
NO2
i) or ii)
NH2
5a R1 = H ; R2 = CH3 ; R3 = NH2
5b R1 = R3 = H ; R2 = n-Bu
7a R1 = H ; R2 = CH3 ; R3 = NH2
7b R1 = R3 = H ; R2 = n-Bu
Scheme 1. Synthesis of N(H)-bridged diaryls 7. Reagents and conditions: (i)
N(iPr)2Et/EtOH/reflux; (ii) Na2CO3/DMSO/rt.
O2N
F
NO2
F
NO2
NH
O2N
F
R1
R2
R3
6
(1 equiv.)
R1
N(iPr)2Et
NH2
wet DMSO
160 °C
R3
R2
7a R1 = H ; R2 = CH3 ; R3 = NH2
7b R1 = R3 = H ; R2 = n-Bu
5a R1 = H ; R2 = CH3 ; R3 = NH2
5b R1 = R3 = H ; R2 = n-Bu
OH-
F-
Figure 1. ORTEP view of the crystal structure of 8a. Displacement parameters
include 50% of the electron density. Selected bond distances (Å) and angles (°):
N(13)–C(1) 1.353(2), C(1)–C(6) 1.434(3), C(6)–N(15) 1.444(3), C(1)–C(2) 1.399(3),
C(3)–O(13) 1.338(3), N(13)–C(7) 1.419(2), C(1)–C(6)–N(15) 122.21(18), C(1)–C(6)–
C(5) 121.66(18), N(13)–C(1)–C(2) 122.61(17), C(2)–C(3)–C(4) 118.87(18), C(3)–
C(4)–N(14) 121.98(19).
NO2
O2N
NH2
NH
H2N
HO
NH
HO
H2 / Pd/C
MeOH
R1
R1
R3
R2
R3
R2
8a R1 = H ; R2 = CH3 ; R3 = NH2
8b R1 = R3 = H ; R2 = n-Bu
the F?OH transformation could not be observed. These observa-
tions clearly established the displacement of the F halogen by di-
rect hydroxylation of 7a and 7b (which do not precipitate in
DMSO or DMF) above 150 °C. This transformation is facilitated by
the presence in 6 of two electron-withdrawing nitro groups (posi-
tioned ortho and para to the substitution site) and by the electron-
withdrawing ipso group (fluoride).
A
air / [Ox]
NH2
NH
H2N
O
NH
NH
H2N
O
H+
Then, the hydrogenation of 8a and 8b on Pd/C furnished the cor-
responding amino species A (not isolated) which under air (i.e.,
upon oxidation) sacrifice their aromatic character in favor of the
target quinones 9a and 9b in 65% and 43% yield, respectively
(Scheme 2).21 Their NMR data are consistent with a quinoid form
as shown for instance by the resonance of the carbonyl group at
180.89 and 180.99 ppm for 9a and 9b, respectively.
R1
R1
R3
R2
R3
R2
10a R1 = H ; R2 = CH3 ; R3 = NH2
10b R1 = R3 = H ; R2 = n-Bu
9a R1 = H ; R2 = CH3 ; R3 = NH2
9b R1 = R3 = H ; R2 = n-Bu
Scheme 2. Synthesis of new benzoquinonemonoimines.
The UV–vis spectrum of molecules 9 is characterized by one
strong absorption at 352 nm and by the presence of a weaker broad
band at 496 nm (Fig. 2). Upon protonation in acetone with HCl, the
absorption spectrum revealed two absorption bands at 369 nm and
612 nm. In both cases, the main absorptions can be attributed to
2). This hypothesis was further confirmed by X-ray analysis19
which clearly established for 8a the presence of the OH group in-
volved in an intramolecular H-bonding interaction between the
O(13)–H proton and O(17) [d(O(13)–HÁ Á ÁO(17)) = 1.914 Å]
(Fig. 1). The structure determination of 8a revealed also the forma-
tion of a single regioisomer for which the CH3 group on the phenyl
ring is located in the para-position with respect to the NH bridge.
This structure determination would suggest that the formation of
8a is controlled by steric effects.
Similarly, the N(H)-bridged diaryls 7b and 8b could be prepared
by condensation between p-nBu–C6H4–NH2 5b and 6 in 25% yield
in refluxing EtOH and 62% yield in DMSO at 160 °C, respectively.18
The formation of 8a and 8b resulting from a Swern-type mech-
anism20 (nucleophilic attack of DMSO on the C–F carbon) could be
excluded since the use of refluxing wet DMF (T = 153 °C) instead of
DMSO furnished also the OH derivatives 8. In contrast, when the
same reaction was performed in refluxing wet CH3CN or EtOH,
the
p–
p⁄ transition of the quinoid skeleton, whereas the weak
absorption band corresponds to a np⁄ transition originating at
the nitrogen lone pair.22 The observed bathochromic effect (i.e.,
drastic color change from red to green) can be explained by the
protonation of the imine function leading to the iminium salt 10
in which the positive charge is stabilized by intramolecular delo-
calization, as already shown on related analogues (Scheme 1).11
In summary, the temperature controlled reactivity places 5 and
6 at the cross-roads of a new versatile strategy for the preparation
of two different categories of N(H)-bridged diaryls 7 and 8. The
F?OH conversion in electron poor diaryls (7) occurs above
150 °C by replacement of the F halogen by the hydroxide anion.
This reaction allows the isolation of the precursors (8) of unprece-
dented quinonemonoimines 9 for which the molecular structure

3680
M. Touil et al. / Tetrahedron Letters 52 (2011) 3678–3680
16. (a) Smith, M. B.; March, J. March’s Advanced Organic Chemistry, 5th ed.; Wiley
Iner-Science: NY, 2001. p 861.2; (b) Cantrell, W. R., Jr.; Bauta, W. E.; Engles, T.
Tetrahedron Lett. 2006, 47, 4249; (c) Bunton, C. A.; Robinson, L. J. Am. Chem. Soc.
1968, 90, 5972; (d) Bunton, C. A.; Robinson, L.; Schaak, J.; Stam, M. F. J. Org.
Chem. 1971, 36, 2346; (e) Broxton, T. J. J. Org. Chem. 1991, 56, 5958; (f) Gallardo,
I.; Guirado, G.; Marquet, J. J. Org. Chem. 2002, 67, 2548; (g) Reis, L. V.; Lobo, A.
M.; Prabhakar, S.; Duarte, M. P. Eur. J. Org. Chem. 2003, 190.
17. (a) Touil, M.; Lachkar, M.; Siri, O. Tetrahedron Lett. 2008, 49, 7250; (b) Touil, M.;
Elhabiri, M.; Lachkar, M.; Siri, O. Eur. J. Org. Chem. 2011, 1914.
18. Synthesis of 7b: To a solution of 4-butylaniline (97 lL, 0.98 mmol, 1 equiv),
diisopropylethylamine (0.34 mL, 1.96 mmol, 2 equiv) in EtOH were added
200 mg (0.98 mmol, 1 equiv) of 1,5-difluoro-2,4-dinitrobenzene. The mixture
was stirred for 30 min at room temperature then was refluxed for 1 h. The
obtained precipitate was isolated by filtration and washed with water
affording 7b as
a
yellow solid (40 mg, 25% yield). Mp = 97 °C. 1H NMR
(250 MHz, CDCl3) d = 0.96 (t, J = 7.30 Hz, 3H), 1.40 (m, 2H), 1.64 (m, 2H), 2.67
3
(t, J = 7.79 Hz, 2H), 6.79 (d, JHF = 13.41 Hz, 1H, aromatic H), 7.18 (d,
Jortho = 8.22 Hz, 2H, aromatic H), 7.32 (d, Jortho = 8.38 Hz, 2H, aromatic H),
4
9.17 (d, JHF = 7.85 Hz, 1H, aromatic H), 9.91 (br s, 1H, NH). MS (ESI)+: [M+H]+
m/z = 334, [M+NH4]+ m/z = 351, [M+Na]+ m/z = 356, [M+K]+ m/z = 372. Anal.
Calcd for C16H16FN3O4Á3/2H2O: C, 53.33; H, 5.31; N, 11.66. Found: C, 53.69; H,
4.86; N, 12.14.
Synthesis of 8a:
A mixture of 1,5-difluoro-2,4-dinitrobenzene (200 mg,
0.98 mmol, 1 equiv), 2,3-diaminotoluene (120.5 mg, 0.98 mmol, 1 equiv) and
Na2CO3 (258 mg, 2.43 mmol, 2.5 equiv) was dissolved in 20 mL of DMSO and
heated at 160 °C for 4 h. The solution was then poured into 40 ml of a mixture
of 40 mL of HCl (1 M) and 50 mL of ethyl acetate and extracted with ethyl
acetate (5 Â 100 mL). The combined organic layers were dried over MgSO4,
evaporated and purified by column chromatography on silica gel using
cyclohexane/ethyl acetate (5:5, Rf = 0.38) to give 8a as a red solid (100 mg,
34% yield). 1H NMR (250 MHz, CDCl3) d = 2.20 (s, 3H, CH3), 3.81 (s, 2H, NH2),
6.57 (m, 1H, aromatic H), 6.59 (s, 1H, aromatic H), 6.60 (d, Jmeta = 2.04 Hz, 1H,
aromatic H), 7.13 (d, Jortho = 7.66 Hz, 1H, aromatic H), 9.17 (s, 1H, aromatic H),
9.77 (s, 1H, NH), 10.93 (s, 1H, OH). MS (MALDI-TOF)+, [M]+ m/z = 304.1. Anal.
Calcd for C13H12N4O5Á1/4C6H12: C, 53.54; H, 4.65; N, 17.22. Found: C, 53.17; H,
Figure 2. UV–vis spectrum of quinonemonoimines in neutral medium (9, red) and
upon protonation (10, green).
opens new perspectives in different fields ranging from biochemis-
try (as bioinhibitors)2–10 to color (as acidochrome)11 and coordina-
tion chemistry (as N3O donor ligands).12
4.36; N, 16.86. IR:
m
C–OH = 1258 cmÀ1
A mixture of 1,5-difluoro-2,4-dinitrobenzene (400 mg,
.
Acknowledgments
Synthesis of 8b:
1.96 mmol, 1 equiv), n-butylaniline (0.31 mL, 1.96 mmol, 1 equiv), and
Na2CO3 (519.3 mg, 4.9 mmol, 2.5 equiv) was dissolved in 20 mL of DMSO and
was heated at 160 °C for 4 h. The solution was then poured into a mixture of
40 mL of HCl (1 M) and 100 mL of ethyl acetate for extraction (5 times). The
combined organic layers were dried over MgSO4, evaporated and purified by
column chromatography on silica gel using cyclohexane/ethyl acetate (9:1,
Rf = 0.43) to give 8b as a red solid (400 mg, 62% yield). Mp = 107 °C. 1H NMR
(250 MHz, CDCl3) d = 0.96 (t, J = 7.36, 3H), 1.40 (m, J = 7.55, 7.36 Hz, 2H), 1.64
(m, 2H), 2.67 (t, J = 7.73 Hz, 2H), 6.54 (s, 1H, aromatic H), 7.20 (d,
Jortho = 8.30 Hz, 2H, aromatic H), 7.31 (d, Jortho = 8.50 Hz, 2H, aromatic H), 9.18
(s, NH), 9.84 (s, OH). MS (ESI)+: [M+H]+ m/z = 332. Anal. Calcd for C16H17N3O5Á6/
5C6H12: C, 64.45; H, 7.32; N, 9.72. Found: C, 64.13; H, 7.28; N, 9.26.
This work was supported by the Centre National de la Recher-
che Scientifique, the Ministère de la Recherche et de l’Enseigne-
ment Supérieur and the Agence Universitaire de la Francophonie
(PhD grant of M.T.). We also thank M. Giorgi for the crystal struc-
ture determination of 8a.
References and notes
1. (a) Xiao, J.; Zhang, Z.; Wu, D.; Routaboul, L.; Braunstein, P.; Doudin, B.; Losovyj,
Y. B.; Kizilkaya, O.; Rosa, L. G.; Borca, C. N. Phys. Chem. Chem. Phys. 2010, 12,
10329; (b) Paretzki, A.; Pattacini, R.; Huebner, R.; Braunstein, P.; Sarkar, B.
Chem. Commun. 2010, 46, 1497; (c) Tamboura, F. B.; Cazin, C. S. J.; Pattacini, R.;
Braunstein, P. Eur. J. Org. Chem. 2009, 20, 3340; (d) Das, H. S.; Weisser, F.;
Schweinfurth, D.; Su, C.-Y.; Bogani, L.; Fiedler, J.; Sarkar, B. Chem. Eur. J. 2010,
16, 2977; (e) Pataï, S.; Rappoport, Z. In The Chemistry of The Quinonoid
Compounds; Wiley and Sons: New York, 1988; Vol. 1,
2. Stahl, P.; Kissau, L.; Matzischek, R.; Giannis, A.; Waldmann, H. Angew. Chem.,
Int. Ed. 2002, 41, 1174.
3. Ling, T.; Poupon, E.; Rueden, E. J.; Kim, S. H.; Theodorakis, E. A. J. Am. Chem. Soc.
2002, 124, 12261.
4. Meazza, G.; Scheffler, B. E.; Tellez, M. R.; Rimando, A. M.; Romagni, J. G.; Duke,
S. O.; Nanayakkara, D.; Khan, I. A.; Abourashed, E. A.; Dayan, F. E. Phytochemistry
2002, 59, 281.
5. Aguilar-Martìnez, M.; Bautista-Martìnez, J. A.; Macìas-Ruvalcaba, N.; Gonzàles,
I.; Tovar, E.; Alizal, T. M. d.; Collera, O.; Cuevas, G. J. Org. Chem. 2001, 66, 8349.
6. Frigaard, N. U.; Tokita, S.; Matsuura, K. Biochem. Biophys. Acta 1999, 1413, 108.
7. Inbaraj, J. J.; Gandhidasan, R.; Murugesan, R. Free Radical Biol. Med. 1999, 26,
1072.
8. Bachur, N. R.; Gordon, S. L.; Gee, M. V. Cancer Res. 1978, 1745.
9. Subbarayudu, N.; Satyanarayana, Y. D.; Venkata-Rao, E.; Venkata-Rao, D. Ind. J.
Pharm. Sci. 1978, 173.
10. Joshi, B. S.; Kamat, V. N. Ind. J. Chem. 1975, 13, 795.
11. Siri, O.; Braunstein, P.; Rohmer, M.-M.; Bénard, M.; Welter, R. J. Am. Chem. Soc.
2003, 125, 13793.
12. (a) Siri, O.; Taquet, J.-p.; Collin, J.-P.; Rohmer, M.-M.; Bénard, M.; Braunstein, P.
Chem. Eur. J. 2005, 11, 7247; (b) Taquet, J.-p.; Siri, O.; Braunstein, P.; Welter, R.
Inorg. Chem. 2006, 45, 4668; (c) Yang, Q.-Z.; Kermagoret, A.; Agostinho, M.; Siri,
O.; Braunstein, P. Organometallics 2006, 25, 5518.
13. Davies, R.; Frahn, J. L. J. Chem. Soc., Perkin Trans. I 1977, 2295.
14. Hooker, J. H.; Esser-Khan, A. P.; Francis, M. B. J. Am. Chem. Soc. 2006, 128, 15558.
15. Corbett, J. F. Hair Colorants: Chemistry and Toxicology; Micelle Press ed., 1998.
19. Crystal data for 8a: monoclinic, space group P21/c with a = 5.3179(2),
b = 17.5462(6), c = 14.6185(5),
a = 90, b = 103.455(2), c = 90 at 293(2) K with
Z = 4, R1 = 0.0582, GOF = 1.141. Crystallographic data for structure 8a have
been deposited at the Cambridge Crystallographic Data Centre (CCDC 785955).
Copy of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +40(0) 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
20. Crich, D.; Neelamkavil, S. Tetrahedron 2002, 58, 3865.
21. General procedure for the synthesis of 9a and 9b: A solution of 8 (80 mg) and
palladium on carbon 5% in 20 mL of methanol was stirred under 60 bar of
hydrogen for 24 h at room temperature, the catalyst was filtered off over celite
and the filtrate was concentrated under vacuum and purified by column
chromatography on silica gel affording 9a and 9b.
Compound 9a: elution in AcOEt/MeOH (9:1, Rf = 0.42) (34 mg 53% yield).
Mp = 175 °C. 1H NMR (250 MHz, CDCl3) d = 2.14 (s, 3H, CH3), 3.70 (s, 2H, NH2),
4.76 (s, 2H, NH2), 5.53 (s, 1H, aromatic H), 6.01 (s, 1H, aromatic H), 6.59 (m, 2H,
aromatic H), 7.03 (d, Jortho = 7.68 Hz, 1H, aromatic H), 8.40 (s, 1H, NH), 9.16 (s,
1H, NH). 13C NMR (62 MHz, CDCl3) d = 16.41, 96.65, 97.04, 108.31, 112.43,
118.98, 130.63, 136.21, 143.20, 144.85, 162.38, 180.89. MS: (ESI)+: [M+H]+ m/
z = 243. Anal. Calcd for C13H14N4OÁ4/15AcOEt: C, 63.57; H, 6.12; N, 21.08.
Found: C, 64.06; H, 6.14; N, 20.63.
Compound 9b: elution in AcOEt (Rf = 0.40) (105 mg, 43% yield). Mp = 172 °C. 1
H
NMR (250 MHz, CDCl3) d = 0.99 (t, J = 7.24 Hz, 3H), 1.39 (m, J = 7.61, 7.51 Hz,
2H), 1.65 (m, J = 7.60, 7.78 Hz, 2H), 2.65 (t, J = 7.80 Hz, 2H), 4.97 (s, 1H,
aromatic H), 5.60 (s, 1H, aromatic H), 6.00 (br s, 2H, aromatic H), 7.22 (d,
J = 1.40 Hz, 2H, aromatic H), 9.10 (s, NH). 13C NMR (62 MHz, CDCl3) d = 13.54,
21.90, 33.17, 34.72, 96.59, 97.17, 122.57, 128.98, 135.12, 139.88, 149.36,
162.48, 180.99; MS (ESI)+: [M+H]+ m/z = 270.1. Anal. Calcd for C16H19N3OÁ1/
5C6H12Á2/5AcOEt: C, 70.25; H, 7.71; N, 13.07. Found: C, 70.09; H, 7.84; N, 13.21.
22. Zhang, R.; Zheng, H.; Shen, J. J. Mol. Struct. 1998, 446, 103.