Synthesis of rigid polycyclic secondary diamines: Bis-(2,3:6,7-iminodimethylene)anthracene and bis-(2,3:6,7-iminodimethylene)-9,10-dicarboxyethenoanthracene

Article abstract of DOI:10.1055/s-2003-40359

The synthesis of two rigid polycyclic secondary diamines, bis-(2,3:6,7-iminodimethylene)anthracene and bis-(2,3:6,7-iminodimethylene)-9,10-dicarboxyethenoanthracene, by means of Diels-Alder reaction between 1,2,4,5-tetra(dibromomethyl)benzene and maleimides followed by imide reduction, is described. Furthermore, these two cyclic secondary diamines undergo acylation with N-protected amino acids, thus providing functionalized, amphiphilic, and chiral building blocks for incorporation into supramolecular systems.

Full text of DOI:10.1055/s-2003-40359

LETTER
1361
Synthesis of Rigid Polycyclic Secondary Diamines: Bis-(2,3:6,7-Imino-
dimethylene)anthracene and Bis-(2,3:6,7-Iminodimethylene)-9,10-dicarboxy-
ethenoanthracene
Synthesis of
R
u
igid Polycyc
m
lic Secondary
D
iam
i
ines ta Bhattacharyya, Jörgen Toftered, Ulf J. Nilsson*
Organic and Bioorganic Chemistry, Lund University, POB 124, SE-221 00 Lund, Sweden
Fax +46(46)2228209; E-mail: ulf.nilsson@bioorganic.lth.se
Received 17 March 2003
Dedicated to the memory of professor Raymond U. Lemieux.
by conversion into the known corresponding anthracene
Abstract: The synthesis of two rigid polycyclic secondary di-
amines, bis-(2,3:6,7-iminodimethylene)anthracene and bis-
(2,3:6,7-iminodimethylene)-9,10-dicarboxyethenoanthracene, by
means of Diels–Alder reaction between 1,2,4,5-tetra(dibromo-
tetracarboxylic acid9 by reflux in 2 M NaOH for 2 hours.
The reduction of 2 was achieved with lithium aluminium
hydride in the presence of aluminium chloride in THF to
methyl)benzene and maleimides followed by imide reduction, is de- give the N,N¢-dibenzyl-derivative 3 in 62% yield. The im-
scribed. Furthermore, these two cyclic secondary diamines undergo
acylation with N-protected amino acids, thus providing functional-
ized, amphiphilic, and chiral building blocks for incorporation into
groups in 3 was accomplished via 1-chloroethyl carbam-
supramolecular systems.
proved solubility of 3 as compared to 2, allowed charac-
terization with NMR and MS. Removal of the benzyl
ate formation10 to give 4, followed by immediate hydrol-
ysis of the crude carbamate 4 in refluxing methanol to
Key words: arenes, amino acids, Diels–Alder reactions, polycycles
afford the diamine hydrochloride 5. The diamine 5 could
alternatively be obtained via a shorter reaction sequence,
Conformationally well-defined and rigid diamino com-
pounds are ideal building blocks possessing reactivity
suitable for high-yielding construction of artificial
receptors1–7 and molecular capsules8 via e.g. amide, urea,
sulfonamide bond forming reactions. Furthermore, it is
desirable that such diamines possess physical properties
(e.g. fluorescence, strong UV-absorption etc.) that allow
for simple monitoring of various molecular events (e.g.
molecular associations). Within this context, rigid polycy-
clic aromatic molecules carrying cyclic secondary amino
groups appear attractive. Herein we report the synthesis of
two novel rigid and fluorescent aromatic secondary di-
amines; bis-(2,3:6,7-iminodimethylene)anthracene and
bis-(2,3:6,7-iminodimethylene)-9,10-dicarboxyethenoan-
thracene, as well as their acylations with amino acids.
These molecules are particularly well suited for incorpo-
ration into supramolecular systems, because they present
a large hydrophobic surface and can be conjugated with
for example amino acids to obtain biomimetic am-
phiphilic properties.
albeit in lower overall yield; BH3·THF/BF3·THF-mediat-
ed reduction of the Diels–Alder aromatisation product 8
between 1 and unsubstituted maleimide gave the free base
9 in 25% yield. With the diamine 5 at hand, its nucleophi-
licity was confirmed by acylation with Na-Boc-glycine
and Na-Fmoc-L-Asp(t-BuO)-OH, which proceeded
smoothly to give 6 (65%) and 7 (75%, Scheme 1).
Br2HC
CHBr2
O
O
a
N
Bn
Bn
N
2
Br2HC
CHBr2
O
O
1
b
g
H
H
N
RN
NR
N
O
O
h
3 R=Bn
c
d
e
4 R=C(O)OCHClCH3
5 R=H.HCl
6 R=COCH2NHBoc
f
The synthesis of N,N¢-diphenyl-2,3:6,7-anthracene de-
scribed by McLaughlin et al.9 provided a starting point for
the present project. The octabromide 19 was subjected to
Diels–Alder aromatisation with N-benzyl maleimide in
the presence of sodium iodide in dimethylacetamide to
give 2 in an acceptable 46% yield. The diimide 2 was
completely insoluble in all solvents available in our labo-
ratory and NMR spectra could not be recorded. The struc-
ture of 2 was finally confirmed by mass spectrometry and
O
7 R=
CO2tBu
FmocHN
O
O
N
H
N
H
8
9
Scheme 1 a) N,N-Dimethylacetamide, NaI, 80 °C, N-benzylmalei-
mide, 46%; b) LiAlH4, AlCl3, THF, reflux, 62%; c) 1-chloroethyl
chloroformate, PhH, (CH2Cl)2; d) MeOH, reflux, 55% over 2 steps;
e) N,N-diisopropylcarbodiimide, 1-hydroxybenzotriazole, THF, H2O,
NaHCO3, Na-Boc-Gly-OH, 65%; f) N,N-diisopropylcarbodiimide, 1-
hydroxybenzotriazole, THF, H2O, NaHCO3, Na-Fmoc-L-Asp-(O-t-
BU)OH, 75%; g) N,N-dimethylacetamide, NaI, 80 °C, maleimide,
30%; h) THF, BH3·THF, BF3·THF, 25%.
Synlett 2003, No. 9, Print: 11 07 2003.
Art Id.1437-2096,E;2003,0,09,1361,1363,ftx,en;S02703ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1362
S. Bhattacharyya et al.
LETTER
to give the crude carbamate 4, which was sufficiently pure for the
next step. The crude 4 was refluxed in MeOH (50 mL) for 24 h. The
diamine hydrochloride 5 precipitated, was filtered, washed with
MeOH, and dried under vacuum (183 mg, 55% from 3). Mp 223–
226 °C. H NMR (400 MHz, D2O): d = 8.40 (s, 2 H, H-9, H-10);
7.92 (s, 4 H, H-1, H-4, H-5, H-8); 4.70 (s, 8 H, 4 CH2). FAB-HRMS:
Dibenzobarrelene frameworks obtained by Diels–Alder
reactions between anthracene derivatives and acetylenes
have proven to be particularly useful building blocks for
the synthesis of water-soluble host molecules.11–15
A
1
dibenzobarrelene framework could be synthesized from
the crude bis-carbamate anthracene 4 by Diels–Alder re-
action with dimethyl acetylene dicarboxylate, followed by
immediate carbamate hydrolysis, to give the diamine 10
(Scheme 2). As for the corresponding anthracene deriva-
tive 5, acylation of 10 with Na-Boc-protected glycine was
straightforward to give 11 in 69%.
m/z calcd for C18H16N2 [M + H]: 260.1313. Found: 260.1353.
bis-[2,3:6,7-(N-Boc-glycyl)iminodimethylene]anthracene (6):
To a solution of 1-hydroxybenzotriazole (101 mg, 0.75 mmol) and
Na-Boc-Gly-OH (128 mg, 0.75 mmol) in dry THF (10 mL), was
added N,N¢-diisopropylcarbodiimide (114 mL, 0.75 mmol). The so-
lution was stirred for 45 min then poured into a solution of 5 (100
mg, 0.30 mmol) in H2O (20 mL), immediately followed by addition
of NaHCO3 (63 mg, 0.75 mmol). After 12 h, the product was ex-
tracted with CH2Cl2, dried (Na2SO4), concentrated, and flash chro-
matographed (SiO2, CH2Cl2/MeOH/Et3N 100:2:1) to give 6 (112
mg, 65%). 1H NMR (400 MHz, CDCl3): d = 8.33 (s, 2 H, H-9, H-
10), 7.85,7.83 (2 s, 4 H, H-1, H-4, H-5, H-8), 5.47 (br s, 2 H, NH),
4.95, 4.89 (2 s, 8 H, ArCH2), 4.02 (bs, 4 H, CH2), 1.41 (s, 18 H,
CH3). FAB-HRMS: m/z calcd for C32H39N4O6 [M + H] 575.2870.
Found 575.2880.
CO2Me
MeO2C
a
4
NR
RN
10 R=H·HCl
11 R=COCH2NHBoc
b
bis-{2,3:6,7-[N-Fmoc-aspartyl(t-BuO)]iminodimethylene}an-
thracene (7) was prepared in 75% yield in a manner similar to that
Scheme 2 a) (i) Dimethyl acetylene dicarboxylate, PhCH3, 120 °C,
(ii) MeOH, reflux, 72%; b) N,N-diisopropylcarbodiimide, 1-hydroxy-
benzotriazole, THF, Na-Boc-Gly-OH, 69%.
1
for 6. H NMR (300 MHz, CDCl3): d = 8.38 (s, 2 H, H-9, H-10),
7.89 (s, 4 H, H-1,H-4, H-5, H-8), 7.77 (d, 4 H, J = 7.4 Hz, FmocH),
7.62 (t, 4 H, J = 6.5 Hz, FmocH), 7.18–7.45 (m, 8 H, FmocH), 5.89
(br d, 2 H, J = 9.5 Hz, NH), 5.07 (br q, 2 H, J = 6.2 Hz, CHCO), 5.02
(s, 8 H, CH2N), 4.42 (m, 4 H, CH2O), 4.24 (br t, 2 H, J = 7.2Hz,
OCH2CH), 2.96 (dd, 2 H, J = 8.1, 16.0 Hz, CH2CO), 2.71 (dd, 2 H,
J = 5.7, 16.0 Hz, CH2CO), 1.46 (s, 18 H, CH3). FAB-HRMS: m/z
calcd for C64H62N4O10Na [M + Na]: 1069.4364. Found: 1069.4397.
In summary, short syntheses towards novel rigid polycy-
clic aromatic secondary diamines, have been developed.
Furthermore, acylation of these amines, i.e. with amino
acids, provided molecules possessing amphiphilic and
chiral properties, which are interesting within the context 2,3:6,7-Anthracenedicarboximide (8) was prepared in 30% yield
in a manner similar to that of 2. Compound 8 was insoluble in or-
ganic solvents. FAB-HRMS: m/z calcd for C18H8N2O4 [M]:
316.0484. Found: 316.0487.
of constructing novel biomimetic host molecules. We en-
vision these diamines to be useful as building blocks for
the construction of various supramolecular systems.
bis-(2,3:6,7-Iminodimethylene)anthracene (9): Compound 8 (1
g, 3.2 mmol) was suspended in dry THF (40 mL) under N2 atmo-
N,N¢-Dibenzyl-2,3:6,7-anthracenedicarboximide (2): To a solu-
tion of 1 (40 g, 52.3 mmol) and N-benzylmaleimide (20 g, 105
mmol) in N,N-dimethylacetamide (500 mL) was added NaI (80 g)
and the mixture was heated at 80 °C for 48 h. The dark solution was
then filtered and washed with H2O and hot dioxane to give 2 as a
bright yellow solid (12 g, 47%), which was stable up to 230 °C and
insoluble in organic solvents. MALDI-TOF-MS; m/z calcd for
C32H20N2O4Na [M + Na]: 519.1. Found: 519.4.
sphere, followed by drop wise addition of BF3·THF (1.7 mL) over
15 min. The mixture was heated to reflux for 2 h. The suspension
was cooled to r.t. and BH3·THF (50 mL, 1 M in THF) was added
over 25 min. The mixture was refluxed for 48 h, cooled to 0 °C,
quenched with HCl (6 M, 15 mL), and refluxed for another 24 h.
The yellow solid was filtered, washed with THF, and then stirred
with water for 2 h. Upon neutralization with aq KOH (6 M), the di-
amine 9 precipitated (395 mg, 25%). 1H NMR (300 MHz, CD3OD):
d = 8.40 (s, 2 H, H-9, H-10), 7.85 (s, 4 H, H-1, H-4, H-5, H-8), 4.75
(s, 8 H, CH2). FAB-HRMS: m/z calcd for C18H16N2 [M]: 260.1313.
Found: 260.1353.
N,N¢-Dibenzyl-bis-(2,3:6,7-iminodimethylene)anthracene (3):
THF (15 mL, dried over LiAlH4) was added to a three-necked round
bottom flask equipped with a reflux condenser. AlCl3 (663 mg, 5
mmol) was added slowly at 0 °C under N2, followed by LiAlH4 (570
mg, 14.2 mmol). To the resulting suspension was added diimide 2
(1.0 g, 2 mmol). The mixture was stirred at r.t. for 1 h, refluxed for
3.5 h, then cooled to r.t., and finally poured onto ice (40 g) in 2 M
NaOH. The THF was evaporated and compound 3 was extracted re-
peatedly into CH2Cl2, dried (Na2SO4) and concentrated. Column
chromatography (SiO2, CH2Cl2/MeOH/Et3N 60:4:1) afforded 4 in
bis-(2,3:6,7-Iminodimethylene)-9,10-dicarboxyethenoan-
thracene (10): To a solution of crude 4 (150 mg, 0.32 mmol) in tol-
uene (4 mL) was added dimethyl acetylenedicarboxylate (900 mL,
20 equiv) under N2 and the solution was then heated to 110 °C in a
sealed tube for 36 h. The excess dimethyl acetylenedicarboxylate
was distilled off and the residue was refluxed in MeOH (30 mL) for
24 h. The mixture was concentrated and flash chromatography
(SiO2, CH2Cl2/MeOH/Et3N 30:4:1→20:4:1 gradient) of the residue
gave 10 (108 mg, 72%). 1H NMR (300 MHz, CD3OD): d = 7.48 (s,
4 H, H-1, H-4, H-5, H-8), 5.63 (s, 2 H, H-9, H-10), 4.54 (s, 8 H,
CH2), 3.76 (s, 6 H, CH3). MALDI-TOF-MS: m/z calcd for
C24H23N2O4 [M + H]: 403.2. Found 403.2.
1
62% yield as a solid that was stable up to 230 °C. H NMR (300
MHz, CDCl3): d = 8.28 (s, 2 H, H-9, H-10), 7.74 (s, 4 H, H-1, H-4,
H-5, H-8), 7.37–7.50 (m, 10 H, Ph), 4.06 (s, 8 H, CH2NCH2Ph),
3.98 (s, 4 H, PhCH2). FAB-HRMS: m/z calcd for C32H29N2 [M + H]:
441.2331. Found: 441.2350.
bis-(2,3:6,7-Iminodimethylene)anthracene hydrochloride (5):
To a solution of compound 3 (500 mg, 1.13 mmol) in 1,2-dichloro-
ethane/benzene (16 mL, 1:1) was added 1-chloroethyl chlorofor-
mate (2.2 mL, 20 mmol) at 0 °C under N2. The reaction mixture was
stirred at r.t. and then refluxed for 24 h. The solvent was evaporated
bis-[2,3:6,7-(N-Boc-glycyl)iminodimethylene]-9,10-dicarboxye-
thenoanthracene (11): To a solution of 1-hydroxybenzotriazole
(7.0 mg, 52 mmol), 10 (10.0 mg, 21 mmol) and Na-Boc-Gly-OH (8.9
mg, 52 mmol) in dry THF (10 mL), was added N,N¢-diisopropylcar-
bodiimide (7.9 mL, 52 mmol). After 12 h, the mixture was concen-
Synlett 2003, No. 9, 1361–1363 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Synthesis of Rigid Polycyclic Secondary Diamines
1363
trated and flash chromatographed (SiO2, CH2Cl2/MeOH/Et3N
100:2:1) to give 11 in (10.4 mg, 69%). 1H NMR (400 MHz,
CD3OD): d = 7.21 (2 br s, 4 H, H-1, H-4, H-5, H-8), 5.41 (s, 2 H,
H-9, H-10), 4.60, 4.51 (2 br s, 8 H, CH2), 1.30 (s, 18 H, CH3).
MALDI-TOF-MS: m/z calcd for C38H44N4O10Na [M + Na]: 739.3.
Found: 739.3.
(4) Hartley, J. H.; James, T. D.; Ward, C. J. J. Chem. Soc.,
Perkin Trans. 1 2000, 3155.
(5) Beer, P. D.; Gale, P. A. Angew. Chem. Int. Ed. 2001, 40, 486.
(6) Lavigne, J. J.; Anslyn, E. V. Angew. Chem. Int. Ed. 2001, 40,
3118.
(7) Fitzmaurice, R. J.; Kyne, G. M.; Douheret, D.; Kilburn, J. D.
J. Chem. Soc., Perkin Trans. 1 2002, 841.
(8) Hof, F.; Craig, S. L.; Nuckolls, C.; Rebek, J. Jr. Angew.
Chem. Int. Ed. 2002, 41, 1488.
Acknowledgment
(9) Morris, J. L.; Becker, C. L.; Fronczek, F. R.; Daly, W. H.;
McLaughlin, M. L. J. Org. Chem. 1994, 59, 6484.
(10) Yang, B. V.; O’Rourke, D.; Li, J. Synlett 1993, 195.
(11) Petti, M. A.; Shepodd, T. J. R. E. B. Jr.; Dougherty, D. A. J.
Am. Chem. Soc. 1988, 110, 6825.
This work was supported by grants from The Swedish Research
Council, The Swedish Strategic Research Foundation, and the pro-
gram ‘Glycoconjugates in Biological Systems’ sponsored by the
Swedish Strategic Research Foundation.
(12) Stauffer, D. A.; Barrans, R. E. Jr.; Dougherty, D. A. J. Org.
Chem. 1990, 55, 2762.
(13) Forman, J. E.; Barrans, R. E. Jr.; Dougherty, D. A. J. Am.
Chem. Soc. 1995, 117, 9213.
(14) Ngola, S. M.; Dougherty, D. A. J. Org. Chem. 1998, 63,
4566.
References
(1) Diedrich, F. Angew. Chem., Int. Ed. Engl. 1988, 27, 362.
(2) Zhang, X. X.; Bradshaw, J. S.; Izatt, R. M. Chem. Rev. 1997,
97, 3313.
(3) Davis, A. P.; Wareham, R. S. Angew. Chem. Int. Ed. 1999,
38, 2978.
(15) Ngola, S. M.; Kearney, P. C.; Mecozzi, S.; Russell, K.;
Dougherty, D. A. J. Am. Chem. Soc. 1999, 121, 1192.
Synlett 2003, No. 9, 1361–1363 ISSN 1234-567-89 © Thieme Stuttgart · New York