Rational synthesis of Ab-type n -substituted core-functionalized naphthalene diimides (cNDIs)

Article abstract of DOI:10.1021/acs.orglett.5b00543

Acid-mediated transformation of tetraethyl 2,6-diethoxynaphthalene-1,4,5,8-tetracarboxylate selectively affords the core-substituted naphthalene-anhydride-ester (cNAE) in quantitative yield. This anhydride can be selectively converted into hetero-N-substituted core-functionalized naphthalene diimides (cNDIs) through sequential condensation reactions in the presence of the precursor amine with very high isolated yields over four steps. The approach can be applied to prepare a large variety of heterocyclic, aromatic, and aliphatic heterodiimides.

Full text of DOI:10.1021/acs.orglett.5b00543

Letter
pubs.acs.org/OrgLett
Rational Synthesis of AB-Type N‑Substituted Core-Functionalized
Naphthalene Diimides (cNDIs)
Andrey A. Berezin,† Andrea Sciutto,† Nicola Demitri,§ and Davide Bonifazi*,†,‡
†Namur Research College (NARC) and Department of Chemistry, University of Namur (UNamur), Rue de Bruxelles 61,
5000 Namur, Belgium
‡Department of Pharmaceutical and Chemical Sciences and INSTM UdR of Trieste, University of Trieste, Piazzale Europa 1,
34127 Trieste, Italy
§Elettra − Sincrotrone Trieste, S.S. 14 Km163.5 in Area Science Park, 34149 Basovizza, Trieste, Italy
S
* Supporting Information
ABSTRACT: Acid-mediated transformation of tetraethyl 2,6-diethoxynaphthalene-1,4,5,8-tetracarboxylate selectively affords the
core-substituted naphthalene-anhydride-ester (cNAE) in quantitative yield. This anhydride can be selectively converted into
hetero-N-substituted core-functionalized naphthalene diimides (cNDIs) through sequential condensation reactions in the
presence of the precursor amine with very high isolated yields over four steps. The approach can be applied to prepare a large
variety of heterocyclic, aromatic, and aliphatic heterodiimides.
hanks to the vigorous organic synthetic developments
two amines.4,14,15 This synthetic approach yields statistical
Tachieved during recent years, core-substituted naph- mixtures of the N-substituted cNDIs (the A2, AB, and B2
derivatives), the distribution of which depends on the reactivity
of the employed amines. Typically, this protocol affords the
desired AB N-substituted cNDIs in modest yields. The
difficulty in accessing large quantities of such N-substituted
cNDIs is, in our opinion, one of the last synthetic constraints
precluding the extensive use of these exceptional chromophores
in the development of covalent and noncovalent functional
architectures of increased complexity.
Herein we thus describe the first rational synthesis for
preparing AB N-substituted cNDIs in very high isolated yields.
The main precursor for the 2,6-diethoxy NDI is tetraethyl 2,6-
diethoxynaphthalene-tetracarboxylate 4,4,14 which was prepared
following a modified synthetic route (Scheme 1 and Supporting
Information (SI)). Bromination (see SI for the details) of
commercial NDA 1 with dimethyl dibromohydantoin followed
by alkylation with Me2SO4 gave tetramethyl 2,6-dibromo-
naphthalene tetracarboxylate 3 in 36% yield. Subsequent
reaction of dibromonaphthalene 3 with EtONa gives
diethoxynaphthalene derivative 4 in 84% yield.
thalenediimides (cNDIs) now cover an impressive spectrum
of structures of tunable properties.1,2 In particular, the ability of
cNDIs bearing electron-donating groups to absorb and
fluoresce light through all the visible spectroscopic region3,4
and of cNDIs equipped with electron-withdrawing groups
to display unprecedented π-acidity5 make these molecular syn-
thons outstanding functional modules for preparing a broad
range of materials6,7 for different applications, such as organic
field-effect transistors (OFETs),8 emissive devices,9 artificial
photosynthetic systems,4,10 n-type semiconductors,6,11 and
organocatalysis.12
Extensive synthetic investigations during recent decades were
mainly focused on gaining control over the chemo- and
regioselective functionalization of the naphthalene core through
aromatic nucleophilic substitution reactions, to prepare a broad
range of sophisticated cNDIs derivatives.2 However, high-
yielding, rationally designed, synthetic methodologies for
preparing cNDIs featuring different N-substituted imidic
moieties (AB) have not been developed so far. Whereas
homo- (A2) N-substituted NDIs are easily obtained with
primary alkyl or aryl amines starting from the precursor core-
substituted naphthalenedianhydride (cNDA),13 AB N-substi-
tuted cNDIs are typically prepared by statistical condensation
reactions of a given cNDA in the presence of a mixture of the
As shown in Scheme 1, we found that tetraethyl ester 4 could
be selectively transformed into core-substituted naphthalene
Received: February 21, 2015
Published: March 30, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00543
Org. Lett. 2015, 17, 1870−1873

Organic Letters
Letter
monoanhydride (cNAE) 5 under reflux conditions in a 5:1
solution of AcOH and aq. conc. HCl (37%) in 2 h
(a quantitative conversion could be obtained after 24 h).
cNAE 5 was isolated first as a minor product from the solvolysis
reaction of tetraethyl ester 4 in refluxing AcOH in the presence
of catalytic amounts of aq. HCl. Suitable single crystals for
X-ray crystallography analysis were obtained by recrystalli-
zation from hot EtOH. The molecular structure, depicted in
Scheme 1, nicely reveals the presence of the anydride and bis-
ester functional groups. Remarkably, the same reaction
conditions can also be applied for gram-scale synthesis, giving
pure product 5 after removal of the solvents. However, reaction
of tetraethyl and tetramethyl 2,6-dibromonaphthalene-1,4,5,8-
tetracarboxylates in refluxing AcOH with HCl did not afford
any monoanhydrides after 24 h, returning only the starting
materials in quantitative yields.
Scheme 1. Synthesis of cNAE 5 and Its ORTEP
Representation as Determined by X-ray Diffraction Analysis
a
(Space Group P21/c)
Having large quantities of cNAE 5 in hand, we could then
undertake the synthesis of a series of core-substituted mono-
imides (cNIEs) 6 using aliphatic, aromatic, or heterocyclic
amines (Table 1).
Refluxing cNAE 5 in EtOH with BnNH2 in the presence of
Et3N afforded cNIE 6a in 56% yield (tetraester 4 deriving from
alcoholysis was also isolated, entry 1). By switching to an
aprotic solvent such as 1,4-dioxane, cNIE 6a was obtained in
87% yield (entry 2). Lower yields were obtained in CH3CN
(entry 3). Interestingly, n-BuNH2 in dioxane produced cNIE 6b
in 40% yield (entry 4). Replacement of Et3N with Hunig’s base
(diisopropylethylamine, HB) afforded the N-alkylated cNIE
product in 92% yield after 2 h under reflux (entry 5). Similar
results were also obtained with BnNH2 that, in dioxane and in
the presence of HB, afforded cNIE 6a in quantitative yield
(entry 6). The condensation reaction with sterically hindered
a
Atomic displacement parameters (223 K) are drawn at the 30%
probability level.
a
Table 1. Optimization of the Reaction Conditions for Preparing cNIEs 6a−e
entry
R1
base
Et3N
additive
solvent
EtOH
t (°C)
time (h)
yield (%)
f
1
Bn-
Bn-
Bn-
−
−
−
−
−
−
−
−
−
78
101
82
1
1
6a (56)
2
Et3N
1,4-dioxane
MeCN
6a (87)
6a (74)
3
Et3N
1
g
4
n-Bu-
Et3N
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
mesitylene
1,4-dioxane
DMF
101
101
101
101
165
101
110
101
110
110
150
150
150
150
5
6b (40)
5
n-Bu-
Hunigs base
Hunigs base
Hunigs base
Hunigs base
Hunigs base
2
6b (92)
6a (98)
6c (64)
6
Bn-
2
7
cyclohexyl-
cyclohexyl-
4-t-BuPh-
4-t-BuPh-
4-t-BuPh-
4-t-BuPh-
Py-4-yl-
Py-4-yl-
Py-4-yl-
24
2
h
8
6c (34)
g
9
12
6
6d (0)
cd
c
c
,
10
11
12
13
14
15
16
17
Et3N
Et3N
Et3N
Et3N
Et3N
−
benzoic acid
benzoic acid
−
6d (92)
c
g
1,4-dioxane
DMF
24
24
48
20
12
12
12
6d (0)
6d (57)
c
c
c
c
g
benzoic acid
DMF
6e (0)
h
benzoic acid
DMF
6e (0)
e
zinc acetate
zinc acetate
quinoline
quinoline
quinoline
6e (41)
6e (55)
6e (30)
b
Py-4-yl-
−
Et3N
c
c
Py-4-yl-
benzoic acid
a
Reaction conditions of NAI 5 (0.23 mmol) with the selected amine (1.1 equiv) in the presence of a base (1.1 equiv) and an acidic additive
(1.1 equiv). 2.2 equiv. 0.6 equiv. Literature conditions.16 Literature conditions.17 The product of alcoholysis to tetraester 4 was isolated.
b
c
d
e
f
g
h
Starting material 5 was recovered. Decomposition of starting material 5 was observed.
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Organic Letters
Letter
a
cyclohexylamine in dioxane required a longer time to reach
complete conversion. The reaction afforded cNIE 6c in 64%
yield after 24 h under reflux conditions (entry 7). In mesitylene
at 165 °C, cNIE 6c was obtained only in 34% yield (entry 8).
An evident decomposition of the starting cNAE material was
also observed. When 4-tert-butylaniline was used, no conversion
was observed after 12 h under the same reaction conditions
as those used for the aliphatic amines (entry 9). However,
following the protocol developed by Ponomarev and co-
workers16 for the synthesis of N-aryl-1,8-naphthalimide, N-
substituted monoimide cNIE 6d could be obtained in very high
yields (92%) in the presence of Et3N and benzoic acid in DMF
at 110 °C over 6 h (entry 10). cNIE 6d was also obtained in
DMF in the absence of benzoic acid, but with much lower
yields (57%) after 24 h at 110 °C (entry 12). Notably, no
conversion was observed when cNAE 5 was refluxed in dioxane
with 4-tert-butylaniline for 24 h (entry 11). Reaction of NAE 5
with 4-amino-pyridine in the presence of Et3N and benzoic
acid gave no conversion even after 48 h in DMF at 110 °C
(entry 13). However, by following literature conditions,17 using
Zn(OAc)2 and quinolone gave us desired cNIE 6e in 41% yield
after 12 h at 150 °C (entry 15). Doubling the equivalents
of 4-amino-pyridine slightly increased the yield up to 55%
(entry 16). Significantly lower yields were obtained in the
absence of Zn(OAc)2 (entry 17). From these studies, three
optimized preparative imidation methods were thus developed
for the alkylic (method Alk, entry 5 or 6), aromatic (method
Ar, entry 10), and heterocyclic (method Het, entry 10) imides.
As shown in Scheme 2, the as-produced cNIEs 6 were then
quantitatively converted into the corresponding naphthalene
Scheme 3. Synthesis of cNDIs 8x from cNAIs 7x
a
Method Alk: Hunig’s base, dioxane, 101 °C 2 h; Method Ar: Et3N,
benzoic acid, DMF, 110 °C, 6 h; Method Het: Zn(OAc)2, quinoline,
150 °C, 12 h; *additional reflux in AcOH for 1 h.
Scheme 4. Imidation of cNAIs 7a, d with Nα-Acetyl-L-lysine
Methyl Ester Hydrochloride and 4-Aminobenzeneboronic
Acid Pinacol Ester
Scheme 2. Conversion of cNIEs 6 into cNAIs 7
this methodology, by varying the amine and the cNAI
substrates. As outlined in Scheme 4, we also reacted cNIAs
with functional amines, such as Nα-Acetyl-L-lysine methyl ester
and 4-amino-phenylboronic pinacol ester. By following
methods Alk and Ar for the lysine and phenylboronic ester,
respectively, cNAIs 7d and 7a were transformed into cNDIs 8d
and 8e with good yields (Scheme 4).
The synthetic approach proposed here also allowed the
preparation of dimeric cNDIs (dcNDIs) 8f, in which the
naphthalene dimide cores are bridged through a 1,4-phenylene
spacer. As outlined in Scheme 5, we followed two orthogonal
synthetic pathways. In the first avenue, reaction of cNAE 5 with
1,4-phenylenediamine under the conditions of method Ar
afforded dimeric tetraester 6f (dcNIE). Solvolysis and con-
densation of dcNIE selectively afforded dianydride 7f (dcNDA)
that, subjected to the conditions of method Alk in the presence
of BnNH2, gave dimer cNDIs 8f (dcNDIs) in 56% yield.
Alternatively, dcNDIs 8f could also be obtained in 78% yield
in one reaction step from cNAI 7a in the presence of 1,4-
phenylenediamine following method Ar.
imide anhydrides (cNAIs) 7 after 24 h in neat TFA under
reflux. Notably, all the aliphatic, aromatic, and heteroaromatic
imides were revealed to be stable under the reaction conditions
showing no apparent decomposition.
By following the optimized imidation protocols as described
above, precursor cNAIs could be transformed into the
corresponding AB N-substituted cNDAs. In particular, applying
method Alk for BnNH2, Ar for 4-tert-butylaniline, and Het for
4-amino-pyridine, we selectively prepared cNDIs 8a−c
following two orthogonal synthetic pathways (Scheme 3).
Notably, no imide scrambling was observed under any of the
employed conditions. It is worth pointing out that while
N-substituted alkyl and aromatic cNAIs 7a and d display similar
reactivity with all the amines, cNAI 7e reacts with BnNH2
following method Alk to give an insoluble product, which we
tentatively assigned to an amide-carboxylic intermediate. Fur-
ther refluxing in AcOH turned out to be necessary to obtain
desired cNDI 8b.
In conclusion, we developed the first rational synthesis of
hetero-N-substituted cNDIs. Three different protocols were
established for the preparation of N-substituted aliphatic,
After the optimized reaction conditions were determined, the
attention was then focused toward examining the generality of
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ASSOCIATED CONTENT
* Supporting Information
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Petrovskii, P. V.; Starikova, Z. A. Russ. Chem. Bull. 2011, 60, 512−520.
■
S
(17) (a) Wurthner, F.; Sautter, A.; Schmid, D.; Weber, P. J. A.
̈
Experimental procedures and spectroscopic data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Chem.Eur. J. 2001, 7, 894−902. (b) Inari, T.; Yamano, M.; Hirano,
A.; Sugawa, K.; Otsuki, J. J. Phys. Chem. A 2014, 118, 5178−5188.
AUTHOR INFORMATION
Corresponding Author
■
*davide.bonifazi@unamur.be
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the European Commission
through the ERC Starting Grant “COLORLANDS”, the FRS-
FNRS (FRFC Contract No. 2.4.550.09), the Science Policy
Office of the Belgian Federal Government (BELSPO-IAP 7/05
project), and the MIUR (FIRB Futuro in Ricerca SUPRA-
CARBON, Contract No. RBFR10DAK6).
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