A facile route to functionalized naphthalimide dyes via copper-catalyzed C-N, C-O, and C-S cross-coupling reactions in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2013.07.010

A mild, facile, and efficient synthesis of fluorescent naphthalimide dyes via CuI-catalyzed CN, CO, and CS Ullman-type condensation reactions using amines, alcohols, and thiols is described. The reactions were carried out in the presence of KF/Al₂O₃ as a mild basic support in water as a green solvent. This protocol tolerates a wide range of functional groups and provides functionalized naphthalimide dyes in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2013.07.010

Accepted Manuscript
A facile route to functionalized naphthalimide dyes via copper-catalyzed C-N,
C-O, and C-S cross-coupling reactions in aqueous medium
Ghasem Rezanejade Bardajee
PII:
S0040-4039(13)01149-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.010
TETL 43208
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
17 February 2013
16 June 2013
2 July 2013
Please cite this article as: Bardajee, G.R., A facile route to functionalized naphthalimide dyes via copper-catalyzed
C-N, C-O, and C-S cross-coupling reactions in aqueous medium, Tetrahedron Letters (2013), doi: http://dx.doi.org/
10.1016/j.tetlet.2013.07.010
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1
Graphical Abstract
A facile route to functionalized naphthalimide dyes via copper-catalyzed C-N, C-O,
and C-S cross-coupling reactions in aqueous medium
Ghasem Rezanejade Bardajee*
R
R
R' X
O
O
O
O
N
O
O
N
O
RNH2
CuI, KF/Al2O3
1,4-dioxane, reflux
H2O
14 examples
70-95%
Br
Br
X
R'
X = NR'', O, S
2
3
4
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A facile route to functionalized naphthalimide dyes via copper-catalyzed C-N,
C-O, and C-S cross-coupling reactions in aqueous medium
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Ghasem Rezanejade Bardajee*
6
Department of Chemistry, Payame Noor University, PO Box 19395-3697, Tehran, Iran
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ABSTRACT
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A mild, facile and efficient synthesis of fluorescent naphthalimide dyes via CuI-catalyzed C-N,
C-O and C-S Ullman-type condensation reactions using amines, alcohols and thiols is described.
The reactions were carried out in the presence of KF/Al2O3 as a mild basic support in water as a
green solvent. This protocol tolerates a wide range of functional groups and provides
functionalized naphthalimide dyes in good to excellent yields.
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Keywords: Aqueous medium; Carbon-heteroatom bond formation; Copper-catalyzed reaction;
Naphthalimide dyes.
*
Corresponding author. Tel.: +98 281 3336366; fax: +98 281 3344081.
E-mail address: rezanejad@pnu.ac.ir (G.R. Bardajee).
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Carbon-heteroatom bond-forming reactions are widely used in industry and academia, in
pharmaceutical research, materials synthesis, and process development. The transition metal
catalyzed cross-coupling reaction of a heteroatom nucleophile and an aryl halide has gained
significant interest.1-4 The products of such transformations are often found as fine chemicals,
dyes and polymers. This importance has led to the development of many synthetic
methodologies for the production of the title compounds. Amongst them, the classical copper-
mediated Ullman coupling, and the recently developed Pd(0)-catalyzed aryl coupling reactions
are commonly used methods. Buchwald et al. adopted this chemistry for the selective N- or O-
arylation of amino alcohols and the C- or N-arylation of oxindoles.5 Although the transition
metal catalyzed reaction of aryl halides and nucleophiles has become an important method for
laboratory scale synthesis, the discovery of new strategies is still desirable.
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1,8-Naphthalimide derivatives are highly fluorescent and photostable, and they have wide
applications in fluorescent synthetic polymers, as textiles and fluorescent solar energy collectors,
as liquid-crystal additives, as electro-optically sensitive materials, in laser technology and as
fluorescent markers in medicine and biology.6-17 For example, compounds of type 1a have been
used with considerable success as intracellular markers in a wide variety of systems (Figure 1).18
Furthermore, naphthalimide 1b has been used for monitoring the interactions between single
stranded desoxyribonucleic acids and proteins.19 In continuation of our interest in studying the
aspects of the morphology and miscibility between polymeric phases, we recently attached
fluorescent compounds of type 1c (Figure 1) as donor and acceptor pairs to polymers.20-22 Also,
we applied dyes of type 1d as atom transfer radical polymerization (ATRP) initiators for the
synthesis of chromophore-labeled poly(2-N,N-dimethylaminoethyl methacrylate) homopolymers
(PDMA) for use in surface modification of CdSe quantum dots.23 Thus, several approaches have
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been developed for their syntheses, some of which suffer from various disadvantages.18,24 Also
some of these methods suffer from a lack of generality for common nucleophiles such as amines,
alcohols and thiols.13-17
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Fig. 1.
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It might therefore be expected that a one-step, straightforward and generally applicable
protocol for the construction of this framework would find significant utility in organic synthesis.
Herein we report a mild, versatile and efficient procedure for the copper iodide catalyzed
synthesis of naphthalimide dyes 4 via carbon-heteroatom bond formation in water as a green
medium and KF/Al2O3 as a heterogeneous basic support (Scheme 1).
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The dyes in the present study were obtained according to Scheme 1. In the first step of
the reaction, 4-bromo-1,8-naphthalic anhydride (2) was reacted with n-butylamine or
isobutylamine in boiling 1,4-dioxane for the appropriate time interval to give intermediates 3
(Scheme 1).20 Good yields of the intermediates 3 were obtained with n-butylamine (76%) and
isobutylamine (74%), but the reaction failed with hindered amines such as tert-butylamine. In the
second step of the synthesis, intermediates 3 were reacted with nucleophiles such as primary or
secondary amines, alcohols and thiols in the presence of copper iodide and KF/Al2O3 in aqueous
medium. Both steps were monitored by thin-layer chromatography (TLC) on silica gel eluting
1
with n-hexane-acetone (3:1). The dyes were characterized by m.p. and IR, H NMR and 13C
NMR spectroscopy and by elemental analysis.
Scheme 1.
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To optimize this reaction, we initially investigated the reaction of 4-bromo-N-
butylnaphthalimide (3a) and butylamine in acetonitrile under various reaction conditions. First
the reactions of 3a and butylamine in the presence of palladium sources such as PdCl2 and
Pd(OAc)2 were investigated. However, these conditions led to only the biaryl side product
resulting from homo-coupling and the desired product was not observed (Table 1, entries 1 and
2). Replacing palladium with copper catalysts such as CuBr and CuI led to an improvement in
the reactivity (Table 1, entries 3 and 4). Adding a ligand such as 1,10-phenanthroline (Phen) or
N,N,N,N-tetramethyl ethylenediamine (TEMED) to enhance the catalytic activity of CuI did not
lead to satisfactory yields (Table 1, entries 5 and 6). Different solvents including 1,4-dioxane,
N,N-dimethylformamide, ethanol and water were tested as the reaction medium (Table 1, entries
7-10). Gratifyingly, the desired product was obtained in 85% GC yield in water as a green
reaction medium (83% isolated yield, Table 1, entry 10). In the next step, the amount of the
KF/Al2O3 was varied to find the optimum amount of support (Table 1, entries 11 and 12).
Accordingly, when the 4-bromo-N-butylnaphthalimide (3a) (0.5 mmol, 1 equiv) was treated with
n-butylamine (1.5 mmol, 3 equiv) in the presence of copper iodide (10 mol%) and KF/Al2O3
(0.10 g) in water (3 mL) for about two hours at 95 °C, the naphthalimide dye 4a was obtained in
83% yield (Table 1, entry 10).
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Table 1.
Using the optimized conditions, we next examined the generality of this protocol for the
construction of a variety of functionalized naphthalimide dyes, using various amines, alcohols
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and thiols. A wide range of nucleophiles including primary and secondary amines, alcohols and
thiols were examined and the results are summarized in Table 2.
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The reactivity of the amines was mainly influenced by steric effects. Generally, primary
amines such as n-butylamine, benzylamine and isobutylamine gave higher yields compared with
secondary amines (Table 2, entries 1-5). Reactions of hindered diisopropylamine, tert-
butylamine or highly conjugated diphenylamine with compound 3a were not successful and no
product was obtained, even after long reaction times. The reaction of 3a with heterocyclic
amines such as piperidine, morpholine and pyrrolidine resulted in the desired naphthalimide dyes
in excellent yields (Table 2, entries 6-8). These higher reactivities can be attributed to the high
nucleophilicity of these heterocyclic amines. Furthermore, the reaction of 3a with bifunctional
amines such as ethanolamine and N-methylethanolamine were highly regio-selective and only
the hydroxyethyl amine derivatives were obtained in high yields (Table 2, entries 9 and 10).
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Table 2.
Next the scope of this reaction to construct C—O and C—S bonds using alcohols and
thiols as nucleophiles was investigated. The results showed that the same catalytic system was
suitable for constructing these structural motifs (Table 2, entries 11-14). The results showed that
the primary alcohols, benzyl alcohol and n-butyl alcohol, gave the desired products in high
yields, but in longer reaction times (Table 2, entries 11 and 12). A similar result was obtained
with ethylene glycol as a bifunctional nucleophile (Table 2, entry 13). However, more hindered
isopropyl and tert-butyl alcohols were not successful under the present reaction conditions. The
reaction of 3a with benzyl mercaptan gave the expected product in high yield (Table 2, entry 15).
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In summary, we have described a novel and highly efficient protocol for the synthesis of
a series of fluorescent naphthalimide dyes in the presence of copper iodide as the catalyst. This
protocol avoids the use of toxic organic solvents and harsh reaction conditions. Furthermore, the
procedure offers several advantages including cleaner reactions, general applicability, improved
yields and simple experimental procedures, which should make it a useful strategy in
naphthalimide dye synthesis.
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Acknowledgments
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Payame Noor University is thanked for financial support of this work.
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Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/....
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3
8. Venkataraman, V. K. In The Chemistry of Synthetic Dyes; Academic Press: New York,
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21. Bardajee, G. R.; Vancaeyzeele, C.; Haley, J. C.; Li, A. Y.; Winnik, M. A. Polymer 2007,
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23. Wang, M.; Bardajee, G. R.; Kumar, S.; Nitz, M.; Scholes, G. D.; Winnik, M. A. J.
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Captions:
Fig. 1. Naphthalimide dyes with different applications
Scheme 1.
Table 1. Screening of the reaction conditions for the cross-coupling reaction of n-butylamine
a
with 4-bromo-N-buthylnaphthalimide (3a) in the presence of KF/Al2O3
Table 2. Synthesis of 1,8-naphthalimide dyes from the reactions of different nucleophiles with
compounds 3 in the presence of KF/Al2O3
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3
Table 1
Screening of the reaction conditions for the cross-coupling reaction of n-butylamine with 4-
a
bromo-N-buthylnaphthalimide (3a) in the presence of KF/Al2O3
Temp Yield
Entry Solvent
Catalyst
PdCl2
Pd(OAc)2 PPh3
CuBr
CuI
Ligand
PPh3
KF/Al2O3 (g)
(°C) (%)b
1
2
3
4
5
6
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
0.1
0.1
0.1
0.1
0.1
80
80
80
80
80
80
100
110
76
95
95
95
—
—
15
61
24
28
66
72
—
—
CuI
CuI
Phen
TEMED 0.1
7
1,4-Dioxane CuI
—
—
—
—
—
—
0.1
0.1
0.1
0.1
0.05
0.15
8
9
10
11
12
DMF
EtOH
H2O
H2O
CuI
CuI
CuI
CuI
CuI
51
85 (83)c
64
H2O
85
4
5
6
7
8
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a All reactions were run under the following conditions: 4-bromo-N-butylnaphthalimide 3a (0.5
mmol, 1 equiv), n-butylamine (1.5 mmol, 3 equiv), catalyst (10 mol%), KF/Al2O3 (0.05-0.15 g),
solvent (3 mL), heating in a sealed tube, 2 h.
b GC yield.
c Isolated yield in parentheses.
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1 Table 2
2 Synthesis of 1,8-naphthalimide dyes from the reactions of different nucleophiles with compounds
3 3 in the presence of KF/Al2O3
Entry
Substratea
Nucleophile
Productb
Yield (%)c
1
83
3a
NH2
2
3
NH2
85
91
3b
3b
4
70d
3a
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5
6
71d
3a
3a
92
95
7
3a
8
95
3a
3b
3b
9
84d
10
80d
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11
81d
3a
12
13
78d
3a
3b
72d
O
N
O
14
82
3b
S
HS
4n
1
2
3
4
5
6
7
8
a The syntheses of compounds 3a,b and the KF/Al2O3 support are reported elsewhere.20,25
1
b All products were characterized by m.p., IR, and H NMR, and their physical data were similar
to those reported in the literature.18,20,24
c
The reactions were run under the following conditions: naphthalimide 3 (0.5 mmol),
nucleophile (1.5 mmol), CuI (10 mol%), KF/Al2O3 (0.10 g), H2O (3 mL), heating in a sealed
tube at 95 °C, 2 h.
d The reaction times were 4 h.
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Figure 1.
3
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R
N
R
N
O
O
O
O
O
O
O
RNH2
Nucleophile (Nu)
KF/Al2O3, H2O, heat
1,4-dioxane, reflux
Nu
Br
2
Br
4
3
3a R= n-Bu
3b R= i-Bu
1
2
Scheme 1.
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