Synthesis and characterization of N-alkyl 1,3-diamino-4,6-diamidobenzenes

Article abstract of DOI:10.1016/j.tetlet.2008.11.089

A new preparation of N-substituted 1,3-diamino-4,6-diamidobenzenes has been achieved. This synthesis affords the first N-alkylamino derivatives for which a fine-tuning of the NR¹R² substituents should modify the reactivity of the ami

Full text of DOI:10.1016/j.tetlet.2008.11.089

Tetrahedron Letters 50 (2009) 630–632
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Tetrahedron Letters
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Synthesis and characterization of N-alkyl 1,3-diamino-4,6-diamidobenzenes
*
Claire Seillan, Olivier Siri
Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), UPR 3118 CNRS, Aix-Marseille Université, Campus de Luminy, Case 913, F-13288 Marseille Cedex 09, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2008
Revised 18 November 2008
Accepted 21 November 2008
Available online 27 November 2008
A new preparation of N-substituted 1,3-diamino-4,6-diamidobenzenes has been achieved. This synthesis
affords the first N-alkylamino derivatives for which a fine-tuning of the NR1R2 substituents should modify
the reactivity of the amine functions.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Ligand
Amide
Amine
Introduction of substituent(s) on the benzene ring1,2 has been
the object of extensive studies leading to hundreds of compounds
with tunable changes of the properties depending on the nature of
the substituent(s).3 Among them, N-functionalized benzenes
substituted in positions 1, 2, 4, and 5 have attracted a major inter-
est in organic, supramolecular, and coordination chemistry owing
to the ability of the substituents to act as nucleophiles,4–12 donor
or acceptor sites12, and coordinating moieties,13,14 respectively.
N-substituted 1,2,4,5-tetraaminobenzenes 1 (R = aryl or alkyl)
could be recently isolated15,16 but their use appeared limited ow-
ing to the high ability of these electron-rich arenes to oxidize under
air. In contrast, the 1,2,4,5-tetraamidobenzene analogues of type 2
are much more air-stable due to the presence of the four amido
functions. Such systems could then be used as bis-chelating13 or
non-innocent14 ligands in coordination chemistry but also in
supramolecular chemistry.12 Therefore, it is surprising that the
aromatic system 3a, which combines the structural elements of 1
and 2, has been poorly explored whereas the substitution pattern
of its amino and amido groups should allow their use as ligand
for complexation of metal centers or as building block for non-
covalent interactions by analogy with the 1,3-arylamides.17–20 To
the best of our knowledge, only very few molecules of type 3a have
been reported in the literature and all of them are NR1-substituted
by an aryl group.21,22
R
R
R3
HN
R3
NH
R
O
O
R
R
O
O
O
HN
NH
HN
HN
NH
NH
R2N
R1
3a R2 = H
NR2
HN
R
NH
R
O
R1
R
1
2
3b R2 = alkyl
Their syntheses involved condensation reactions of aromatic com-
pounds which strongly limit the nature of the N-substituents
(R1 = aryl group, R2 = H).21,22 Therefore, an alternative route that
would give access to new 1,3-diamino-4,6-diamidobenzenes of type
3a could be useful to enlarge the scope of this class of molecules. For
instance, the preparation of N–R1 alkyl analogues, hitherto un-
known, should strongly modify the reactivity of the amino groups
in 3a (i.e., their basicity and/or nucleophilic character) owing to
the presence of more electron-donating substituents. As an exten-
sion of this study, further substituted analogues of type 3b, previ-
ously unknown, appear very attractive in the development of new
and tunable 1,2,4,5-tetranitrogenated benzenes.
Herein, we wish to report a new and versatile synthesis of 1,3-
diamino-4,6-diamidobenzenes which allowed the preparation of
the first N-alkyl-substituted compounds of type 3a (R1 = n-Bu),
and N,N0-disubstituted analogues of type 3b.
The commercially available precursor 4 was first reacted with n-
butylamine in refluxing EtOH to afford 5 in almost quantitative yield
(99%) (Scheme 1).23 To the best of our knowledge, although reported
in the literature,24,25 compound 5 has not been fully characterized
* 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 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.089

C. Seillan, O. Siri / Tetrahedron Letters 50 (2009) 630–632
631
R
O
O
R
HN
NH
O2N
NO2
H2N
NH2
H2 / Pd/C / rt
RC(O)Cl
AcOEt /
MeOH
MeCN/reflux
CH3
CH3
H3C
CH3
H3C
H3C
N
N
N
N
N
N
81%
n-Bu
12a
12b R = t-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
11
10
R = Ph
n-BuNHCH3
EtOH / reflux
quant.
O2N
NO2
O2N
NO2
F
O2N
NO2
BOC2O
n-BuNH2
EtOH / reflux
99%
THF / reflux
quant.
HN
NH
F
BOCN
NBOC
n-Bu
n-Bu
n-Bu
5
4
n-Bu
6
H2 / Pd/C / rt
AcOEt / MeOH
97%
Ph
O
O
Ph
NH
NH
n-Bu
Ph
O
O
Ph
HN
HN
HN
NH
H2N
NH2
PhC(O)Cl
TFA, 0°C
43%
MeCN / reflux
69%
BOCN
NBOC
BOCN
NBOC
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
9
8
7
Scheme 1. Synthesis of N-alkyl diamino-diamidobenzenes.
(i.e., including by NMR). The direct reduction of 5 led to the forma-
tion of a large number of unidentified compounds due to the air oxi-
dation of the corresponding diamino derivative and further possible
side reactions such as hydrolysis and co-condensation.26 Introduc-
tion of protective groups was then envisaged in order to prevent
the oxidation of the reduced species. Compound 5 was thus treated
with BOC2O (4 equiv) in refluxing THF in the presence of a catalytic
amount of 4-DMAP to yield quantitatively 6.23 The reduction of the
nitro groups could not be performed with SnCl2 owing to the BOC
deprotection in acidic medium. Compound 6 was then reduced by
catalytic hydrogenation to afford 7 (97% yield),23 which was further
acylated with PhC(O)Cl in refluxing MeCN to allow the isolation of 8
(69% yield).23 Finally, deprotection of 8 in TFA gave access to 9 as a
yellow solid (43% yield).23 Its 1H NMR shows two broad singlets at
4.75 and 9.49 ppm corresponding to the amino and amido NH pro-
tons, respectively. As expected, molecule 9 is air stable due to the
presence of the two amido groups.
key role of the BOC substituents in the formation of two different
conformers for 7. It is noteworthy that the aromatic protons adja-
cent to the amide functions in 12a and 12b are strongly downfield
(d = 9.73 and 9.35 ppm, respectively) by comparison with
9
(d = 6.93 ppm).23 These observations suggest for molecules of type
12 H-bonding interactions between the carbonyl groups of the
amide functions in 4,6-positions and the C–H aromatic hydrogen
[C–Hꢀ ꢀ ꢀO@C].27
R
R
O
O
H
HN
NH
CH3
H3C
N
N
n-Bu
n-Bu
12
This phenomenon can be explained in 12a and 12b by steric hin-
drance of the methyl groups which prevent the rotation of the
(O)C–N bonds. In the case of 9, the amino groups in 1,3-positions
do not affect the amido functions in 4,6-positions allowing the free
rotation of the (O)C–N bonds (no hydrogen bonding interactions in
solution).
Interestingly, the 1H NMR spectrum of 7 shows the presence of
a larger number of signals than expected for a symmetry analogue
to that of 6. Two signals (I = 1) instead of one appear at d = 6.45 and
6.50 ppm for the aromatic proton located between the ‘NBOC’ sub-
stituents. In addition, the NH2 groups appear as two broad singlets
at 4.21 and 4.24 ppm, and the NCH2 methylenic protons as two
broad multiplets at 3.16 and 3.69 ppm. These observations would
suggest the presence of two conformations in equilibrium in solu-
tion resulted from H-bonded interactions involving the BOC groups
and the newly formed NH2 sites. Intermolecular aggregation could
be excluded upon the dilution conditions of the NMR experiments.
The use of secondary amines was also investigated in order to
extend this procedure to a broader applicability. Similarly to the
preparation of 5, molecule 4 was reacted with N-methyl-n-butyl-
amine to yield quantitatively 10 as an orange solid (Scheme 1).23
Its reduction could be achieved by catalytic hydrogenation to af-
ford 11 as a brown oil (81% yield). Acylation reaction of 11 with dif-
ferent acyl groups (R = aryl or alkyl) gave access to 12a or 12b as
yellow oils in 79 and 89% yield, respectively. In contrast to 7, the
1H NMR spectrum of 11 shows a symmetrical geometry in agree-
ment with the presence of one compound in solution and the
In the course of the preparation of unsymmetrical 12p electron
quinones such as 13, molecule 9 appeared to be a precursor of
choice by analogy with the recent synthesis of the closely related
analogue 14.26 However, similarly to 5, the reduction of 9 led to
a large mixture of compounds and despite successive purification
steps, compound 13 could be only identified by 1H NMR among
several by-products.
R2
R2
R2
R1
HN
N
HN
N
N
NH
R1
N
NH
R1
R1
R2
13
14
In summary, we have disclosed a new synthesis of N-substituted
1,3-diamino-4,6-amidobenzenes. The first member of N-alkylamino

632
C. Seillan, O. Siri / Tetrahedron Letters 50 (2009) 630–632
(br s, 4H, NH2), 6.17 (br s, 2H, H2N–C@CH–C–NH2), 6.45 (br s, 1H, N–C@CH–C–
N), 6.50 (br s, 1H, N–C@CH–C–N). MS (ESI)+: m/z = 451 [M+H].+ Anal. Calcd for
C24H42N4O4: C, 63.97; H, 9.39; N, 12.43. Found: C, 63.97; H, 9.60; N 12.36.
Synthesis of 8: To a solution of 7 (0.42 g, 0.94 mmol, 1 equiv) in dry MeCN in the
derivatives (9) has been prepared in five steps with an overall yield
of 28%. N,N0-substituted analogues have been also synthetized with
aryl (12a) or alkyl (12b) acyl group (overall yield up to 72%). The
fine-tuning of the different substituents should enlarge the scope
of this family of molecules by analogy with other N4 donors.28
presence of NEt3 (4 equiv) was dropwise added PhC(O)Cl (330 lL, 2.84 mmol,
3 equiv) under Ar. After stirring under reflux for 12 h, the solvent was evaporated
and the residue was taken up in AcOEt and washed with H2O. The organic layers
were then concentrated and purified by SiO2 chromatography affording 8 a
yellow oil (69% yield). 1H NMR (250 MHz, acetone-d6) d 0.70 (t, 3JHH = 7.2 Hz, 6H,
CH3–CH2), 1.16 (m, 4H, CH3–CH2), 1.30 (br s, 18H, C(CH3)3), 1.38 (m, 4H, CH2),
3.54 (t, 3JHH = 8.0 Hz, 4H, N–CH2), 7.45 (m, 6H, aromatic H), 7.81 (m, 4H, aromatic
H), 7.92 (m, 2H, aromatic H), 8.65 (br s, 1H, NH), 8.80 (br s, 1H, NH). 13C NMR
(62 MHz, acetone-d6) d14.0 (CH3), 20.6 (CH2), 28.4 (C(CH3)3), 31.3 (CH2), 50.5 (N–
CH2), 81.2 (C(CH3)3), 128.0, 129.3, 129.6, 130.4, 132.7, 133.7, 134.9, 135.8
(aromatic C), 155.4 (O–C@O), 165.5 (HN–C@O). MS (ESI)+: m/z = 681 [M+Na]+.
Synthesis of 9: A solution of 8 (0.26 g, 0.40 mmol) in TFA was stirred at 0 °C for 2 h
under Ar. The end of the reaction was monitored by TLC, and TFA was then
evaporated under reduced pressure. The residue was taken up in a saturated
solution of NaHCO3 and extracted with CH2Cl2. The organic layers were then
concentrated before adding acetone. The insoluble suspension was isolated by
filtration affording 9 as a yellow solid (43% yield). 1H NMR (250 MHz, DMSO-d6) d
0.92 (t, 3JHH = 7.2 Hz, 6H, CH3–CH2), 1.39 (sext, 3JHH = 7.2 Hz, 4H, CH3–CH2), 1.57
(qt, 3JHH = 7.2 Hz, 4H, CH2), 3.09 (br q, 4H, N–CH2), 4.75 (t, 2H, H2C–NH), 5.97 (s,
1H, HN–C@CH–C–NH), 6.93 (s, 1H, (O)CN–C@CH–C–NC(O)), 7.51 (m, 6H,
aromatic H), 7.98 (m, 4H, aromatic H), 9.49 (s, 2H, (O)CNH). 13C NMR (62 MHz,
DMSO-d6) d 13.9 (CH3), 19.9 (CH2), 31.1 (CH2), 42.8 (N–CH2), 93.7, 111.9, 126.5,
127.7, 128.3, 131.2, 134.8, 143.3 (aromatic C), 165.8 (C@O). MS (ESI)+: m/z = 459
[M+H].+ Anal. Calcd for C28H34N4O2ꢀ1/3(CH3)2C(O): C, 72.88; H, 7.59; N, 11.72.
Found: C, 72.44; H, 7.60; N, 11.91.
Acknowledgments
This work was supported by the Centre National de la Recher-
che Scientifique, the Ministère de la Recherche et des Nouvelles
Technologies. We also thank the Provence Alpes Côte d’Azur Re-
gion (Grant C.S.).
References and notes
1. Randic, M. Chem. Rev. 2003, 103, 3449.
2. Krygowski, T. M.; Cyranski, M. K. Chem. Rev. 2001, 101, 1385.
3. Vollhardt, K. P. C.; Schore, N. E. Organic Chemistry, 2nd ed. ; W.H. Freeman and
Company: New York, 1994.
4. Weider, P. R.; Hegedus, L. S.; Asada, H.; D’Andreq, S. V. J. Org. Chem. 1985, 50,
4276.
5. Nakagawa, H.; Sei, Y.; Yamaguchi, K.; Nagano, T.; Higuchi, T. J. Mol. Catal. A
2004, 219, 221.
6. Crossley, M. J.; Thordarson, P. Angew. Chem., Int. Ed. 2002, 41, 1709.
7. Loev, B.; Jones, H.; Brown, R. E.; Huang, F. C.; Khandwala, A.; Mitchell, M. J.;
Sonnino-Goldman, P. J. Med. Chem. 1985, 28, 24.
8. Kobayashi, T.; Kobayashi, S. Eur. J. Org. Chem. 2002, 2066.
9. Krill, J.; Shevchenko, I. V.; Fischer, A.; Jones, P. G.; Schmutzler, R. Heteroat. Chem.
1997, 8, 165.
10. Reddy, T. J.; Iwama, T.; Halpern, H. J.; Rawal, V. H. J. Org. Chem. 2002, 67, 4635.
11. Siri, O.; Braunstein, P. Chem. Commun. 2000, 2223.
12. Siri, O.; Braunstein, P.; Rohmer, M.-M.; Bénard, M.; Welter, R. J. Am. Chem. Soc.
2003, 125, 13793.
13. Gordon-Wylie, S. W.; Claus, B. L.; Horwitz, C. P.; Leychkis, Y.; Workman, J. M.;
Marzec, A. J.; Clark, G. R.; Rickard, C. E. F.; Conklin, B. J.; Sellers, S.; Yee, G. T.;
Collins, T. J. Chem. Eur. J. 1998, 4, 2173.
14. Beckmann, U.; Bill, E.; Weyhermüller, T.; Wieghardt, K. Inorg. Chem. 2003, 42,
1045.
15. Wenderski, T.; Light, K. M.; Ogrin, D.; Bott, S. G.; Harlan, C. J. Tetrahedron Lett.
2004, 6851.
16. Khramov, D. M.; Boydston, A. J.; Bielawski, C. W. Org. Lett. 2006, 8, 1831.
17. Rae, I. D. Aust. J. Chem. 1978, 31, 1851.
18. Kavallieratos, K.; Gala, S. R. d.; Austin, D. J.; Crabtree, R. H. J. Am. Chem. Soc.
1997, 119, 2325.
19. Kang, S. O.; Begum, R. A.; Bowman-James, K. Angew. Chem., Int. Ed. 2006, 45,
7882.
20. Doerksen, R. J.; Chen, B.; Liu, D.; Tew, G. N.; DeGrado, W. F.; Klein, M. L. Chem.
Eur. J. 2004, 10, 5008.
21. Korshak, V. V.; Rusanov, A. L.; Tugushi, D. S.; Cherkasova, G. M. Macromolecules
1972, 5, 807.
Synthesis of 10: n-BuMeNH (v = 577
lL, 4.90 mmol, 2 equiv); 4 (m = 500 mg,
2.45 mmol, 1 equiv); NEt(i-Pr)2 (854
l
L, 4.90 mmol, 2 equiv). EtOH was
concentrated under reduced pressure, and the residue was taken up in ethyl
acetate and washed with H2O. The organic layer was then concentrated affording
10 as an orange solid (quantitative). 1H NMR (250 MHz, acetone-d6) d 0.92 (t,
3
3JHH = 7.2 Hz, 6H, CH3), 1.36 (qt, JHH = 7.2 Hz, 4H, CH3–CH2), 1.68 (qt,
3JHH = 7.2 Hz, 4H, CH3–CH2–CH2), 2.91 (s, 6H, N–CH3), 3.31 (t, 3JHH = 7.2 Hz, 4H,
N–CH2), 6.43 (s, 1H, N–C@CH–C-N), 8.43 (s, 1H, O2N–C@CH–C–NO2). 13C NMR
(62 MHz, acetone-d6) d 14.0 (CH3), 20.6, 29.7, 40.2 (CH2), 54.3 (CH3), 105.0,
130.20, 130.24, 150.2 (aromatic C). MS (ESI)+: m/z = 339 [M+H]+. Anal. Calcd for
C16H26N4O4: C, 56.79; H, 7.74; N, 16.56. Found: C, 56.52; H, 7.97; N, 16.33.
Synthesis of 11: To a solution of 10 (247 mg, 0.73 mmol, 1 equiv) in a dry mixture
of AcOEt/MeOH (v/v: 1/1) was added 5% Pd/C. The mixture was then stirred at rt
under H2 pressure (P = 20 bars) overnight and filtered on Celite. After
concentration of the solvents, 11 was isolated as a brown oil (81% yield). 1H
NMR (250 MHz, acetone-d6) d 0.87 (t, 3JHH = 7.2 Hz, 6H, CH3–CH2), 1.37 (m, 8H,
CH3–CH2–CH2), 2.50 (s, 6H, N–CH3), 2.75 (t, 3JHH = 7.0 Hz, 4H, N–CH2), 4.21 (br s,
4H, NH2), 6.11 (s, 1H, H2N–C@CH–C–NH2), 6.77 (s, 1H, N–C@CH–C–N). 13C NMR
(62 MHz, acetone-d6) d 14.4 (CH3), 21.1, 30.9, 43.3 (CH2), 57.0 (CH3), 102.0, 114.4,
130.4, 141.6 (aromatic C). MS (ESI)+: m/z = 279 [M+H]+.
Synthesis of 12: To a solution of 11 (1 equiv) in dry MeCN in the presence of
triethylamine (4 equiv) was dropwise added acyl chloride (3 equiv) under argon.
After stirring under reflux overnight, the solvent was evaporated and the residue
was taken up in ethyl acetate and washed with H2O. The organic layers were then
concentrated and purified by SiO2 chromatography affording 12a or 12b.
Compound 12a: 11 (143.4 mg, 0.52 mmol, 1 equiv), NEt3 (v = 290
lL, 2.06 mmol,
22. Berlin, J. K.; Coburn, M. D. J. Heterocycl. Chem. 1975, 12, 235.
4 equiv), PhC(O)Cl (v = 180 L, 1.55 mmol, 3 equiv). The crude product was
l
23. Synthesis of 5: To a solution of n-BuNH2 (v = 490
lL, 4.90 mmol, 2 equiv) in
purified by flash SiO2 chromatography (eluent: cyclohexane/ethyl acetate 10/0,
EtOH were added 4 (m = 500 mg, 2.45 mmol, 1 equiv) and NEt(i-Pr)2 (850
lL,
9/1, 8/2, 7/3) affording 12a as a yellow oil (79%). 1H NMR (250 MHz, acetone-d6) d
4.90 mmol, 2 equiv). The mixture was then stirred at room temperature for 1/
2 h and under reflux for 1 h. The obtained precipitate was then isolated by
filtration affording 5 as a yellow solid (99% yield). 1H NMR (250 MHz, acetone-d6)
3
0.83 (t, JHH = 7.0 Hz, 6H, CH3–CH2), 1.32 (m, 4H, CH3–CH2), 1.48 (m, 4H, CH3–
CH2–CH2), 2.70 (s, 6H, N–CH3), 2.95 (t, 3JHH = 7.0 Hz, 4H, N–CH2), 7.39 (s, 1H, N–
C@CH–C–N), 7.58 (m, 6H, aromatic H), 8.02 (m, 4H, aromatic H), 9.67 (br s, 2H,
NH), 9.73 (s, 1H, HN–C@CH–C–NH). 13C NMR (62 MHz, acetone-d6) d 14.2 (CH3),
21.0, 30.8 (CH2), 43.7 (N–CH3), 57.3 (N–CH2), 111.4, 116.0, 127.7, 129.6, 132.4,
132.95, 136.4, 138.9 (aromatic C), 164.6 (C@O). MS (ESI)+: m/z = 487 [M+H].+
Anal. Calcd for C30H38N4O2ꢀ3/4AcOEtꢀ3/4C6H12: C, 73.14; H, 8.67; N, 9.10. Found:
C, 73.12; H, 8.08; N, 8.69.
3
3
d 0.99 (t, JHH = 7.2 Hz, 6H, CH3), 1.49 (qt, JHH = 7.2 Hz, 4H, CH3–CH2), 1.77 (qt,
3JHH = 7.2 Hz, 4H, CH3–CH2–CH2), 3.45 (td, JHH = 7.2 Hz, JHH = 5.2 Hz, 4H, HN–
CH2), 5.94 (s, 1H, HN–C@CH–C–NH), 8.40 (br s, 2H, NH), 9.07 (s, 1H, O2N–C@CH–
C–NO2). 13C NMR (62 MHz, acetone-d6) d 14.0 (CH3), 20.9, 31.1, 43.5 (CH2), 91.4,
124.6, 129.5, 149.4 (aromatic C). MS (ESI)+: m/z = 311 [M+H]+. Anal. Calcd for
C14H22N4O4: C, 54.18; H, 7.15; N, 18.05. Found: C, 54.14; H, 7.23; N 18.04.
Synthesis of 6: To a solution of 5 (1.00 g, 3.22 mmol, 1 equiv) in dry THF were
added BOC2O (m = 2.84 g, 13.01 mmol, 4 equiv) and 4-DMAP (0.08 g,
0.65 mmol, 0.2 equiv) under Ar. The mixture was then stirred under reflux
for 1 h. After evaporation of the THF, the residue was purified by SiO2
3
3
Compound 12b: 11 (139.4 mg, 0.50 mmol, 1 equiv), NEt3 (v = 280
lL, 2.00 mmol,
4 equiv), t-BuC(O)Cl (v = 185 L, 1.50 mmol, 3 equiv). The crude product was
l
purified by flash SiO2 chromatography (eluent: cyclohexane/ethyl acetate 8/2, 7/
3) affording 12b as a yellow oil (89% yield). 1H NMR (250 MHz, acetone-d6) d 0.74
3
(t, JHH = 7.0 Hz, 6H, CH3–CH2), 1.35–1.15 (m, 26H, CH3-CH2–CH2 and C(CH3)3),
chromatography affording quantitatively
6 as a
yellow solid. 1H NMR
2.50 (s, 6H, N–CH3), 2.78 (t, 3JHH = 7.0 Hz, 4H, N–CH2), 7.12 (s, 1H, N–C@CH–C–N),
8.92 (br s, 2H, NH), 9.35 (s, 1H, HN–C@CH–C–NH). 13C NMR (62 MHz, acetone-d6)
d 14.2 (CH3), 21.0 (CH2), 27.8 (C–CH3), 30.7 (CH2), 40.4 (C), 44.1 (N–CH3), 56.7 (N–
CH2), 110.5, 115.5, 133.3, 137.4 (aromatic C), 175.7 (C@O). MS (ESI)+: m/z = 447
[M+H]+. Anal. Calcd for C26H46N4O2ꢀ1/3AcOEt: C, 68.96; H, 10.30; N 11.77. Found:
C, 69.46; H, 10.71; N, 11.36.
3
(250 MHz, acetone-d6) d 0.91 (t, JHH = 7.25 Hz, 6H, CH3–CH2), 1.50 (m, 26H,
C(CH3)3 and CH3–CH2–CH2), 3.84 (br s, 4H, N–CH2), 7.78 (s, 1H, N–C@CH–C–N),
8.60 (s, 1H, O2N–C@CH–C–NO2). 13C NMR (62 MHz, acetone-d6) d 14.0 (CH3),
20.7 (CH2), 27.9 (C(CH3)3), 31.2 (CH2), 50.7 (N–CH2), 82.6 (C(CH3)3), 123.6,
128.2, 141.7, 143.5 (aromatic C), 152.4 (C@O). MS (ESI)+: m/z = 533 [M+Na]+.
Anal. Calcd for C24H38N4O8: C, 56.46; H, 7.50; N, 10.97. Found: C, 56.90; H, 7.50;
N 10.80.
24. Mustafa, A.; Zahran, A. A. J. Chem. Eng. Data 1963, 8, 135.
25. Winkelmann, V. E.; Raether, W.; Dittmar, W.; Düwel, D.; Gericke, D.; Hohorst,
W.; Rolly, H.; Schrinner, E. Arzneim. -Forsch. (Drug Res.) 1975, 25, 681.
26. Seillan, C.; Braunstein, P.; Siri, O. Eur. J. Org. Chem. 2008, 3113.
27. Niebel, C.; Lokshin, V.; Sigalov, M.; Krief, P.; Khodorkovsky, V. Eur. J. Org. Chem
2008, 3689.
Synthesis of 7: To a solution of 6 (1.14 g, 2.23 mmol, 1 equiv) in a dry mixture of
AcOEt/MeOH (v/v: 1/1) was added Pd/C (5%). The mixture was then stirred at rt
under H2 pressure (P = 20 bars) for 2 h and filtered on Celite. After
concentration of the solvents, 7 was isolated as a brown solid (97% yield). 1H
3
NMR (250 MHz, acetone-d6) d 0.80 (br t, JHH = 7.2 Hz, 12H, CH3–CH2), 1.30–
28. Siri, O.; Taquet, J.-p.; Collin, J.-P.; Rohmer, M.-M.; Bénard, M.; Braunstein, P.
Chem. Eur. J. 2005, 11, 7247.
1.40 (br m with br s, 44H, CH3–CH2 and C(CH3)3), 1.48 (br m, 8H, CH3–CH2–
CH2), 3.16 (br m, 4H, N–CH2), 3.69 (br m, 4H, N–CH2), 4.21 (br s, 4H, NH2), 4.24