Synthesis of N-substituted 4-hydroxynaphthalimides using palladium-catalysed hydroxylation

Article abstract of DOI:10.1016/j.dyepig.2015.11.007

Successful implementation of a palladium-mediated hydroxylation of N-substituted 4-chloro-1,8-naphthalimides has been achieved. The methodology detailed herein utilises 4-chloro-1,8-naphthalic anhydride as a starting point and implements the catalyst/liga

Full text of DOI:10.1016/j.dyepig.2015.11.007

Dyes and Pigments 126 (2016) 118e120
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Short communication
Synthesis of N-substituted 4-hydroxynaphthalimides using
palladium-catalysed hydroxylation
a
a
,
b
c
a
Cassandra L. Fleming , Tim D. Nalder , Egan H. Doeven , Colin J. Barrow ,
a
a, *
Frederick M. Pfeffer , Trent D. Ashton
Centre for Chemistry and Biotechnology, School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Victoria, 3216, Australia
Marine Products Team, The New Zealand Institute for Plant & Food Research Limited, 300 Wakefield Quay, Nelson, New Zealand
Centre for Regional and Rural Futures, School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Victoria, 3216, Australia
a
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 September 2015
Received in revised form
Successful implementation of a palladium-mediated hydroxylation of N-substituted 4-chloro-1,8-
naphthalimides has been achieved. The methodology detailed herein utilises 4-chloro-1,8-naphthalic
anhydride as a starting point and implements the catalyst/ligand combination of Pd(OAc) /t-BuXPhos;
2
all of which are relatively inexpensive. A range of imide substituents tolerated the reaction conditions,
including acid sensitive substrates which are not compatible with other existing methodology. As such
this approach is not only complimentary to existing procedures, it presents a more direct alternative to
accessing 4-hydroxy-1,8-naphthalimides.
3
November 2015
Accepted 5 November 2015
Available online 22 November 2015
Keywords:
Palladium
©
2015 Elsevier Ltd. All rights reserved.
Hydroxylation
Buchwald-Hartwig
4-Hydroxy-1,8-naphthalimide
Biarylphosphine
Fluorescence
1
. Introduction
approach is precluded by the harsh conditions. Consequently,
-hydroxy-1,8-naphthalimides are typically accessed in two steps
from the 4-chloro or 4-bromo-1,8-naphthalimides. Nucleophilic
aromatic substitution (S Ar) or Ulmann-type reactions using
methanol as a nucleophile gives a methyl aryl ether [4c,6,8] which
is then cleaved using strong acid (HI or HBr) to afford the
4-hydroxy-1,8-naphthalimide [4aec], [6]. Whilst these procedures
are often high yielding, functional group tolerance is impacted
during the demethylation step. Interestingly, in the report by Li
et al., the presence of a N-(2-hydroxyethyl) is enough of a structural
change for the phenol precursor of 3 to require a bespoke synthesis.
Here the 4-bromo-1,8-naphthalimide was initially converted to the
boronic acid pinacolyl ester using bis(pinacolato)diboron and
4
When an amine or hydroxyl is present in the 4-position of 1,8-
naphthalimides an internal charge transfer (ICT) system results
that gives rise to an efficient fluorophore [1]. These 4-substituted
derivatives exhibit excellent photostability, high quantum yields,
large Stokes shifts, and are often cell permeable. As a result the 4-
amino derivatives have been widely adopted for analyte responsive
fluorescent imaging of live cells [2]. More recently the 4-hydroxy-
N
1,8-naphthalimide fluorophore is gaining popularity as a fluores-
cent reporter for the cellular imaging of nitroxyl (1, Fig. 1) [3],
hydrogen sulfide (2, 3) [4], copper (4) [5], and more recently the
solvatochromatic fluorophore 5 was used to quantify H O in
2
organic solvents [6]. Esterification of the hydroxyl analogues results
in hypsochromic shift of the emission maxima which is advanta-
geous in the design of ratiometric probes (e.g. 1 and 4).
Pd(dppf)Cl
the phenol in moderate yield (51%, 35% over two steps) [4c].
single example of direct hydroxylation of 4-chloro-
2 2 2
(69% yield) before hydroboration (H O /NaOH) to give
A
a
One of the earliest reported syntheses of the 4-hydroxy system
1,8-naphthalimide was reported by Bekere et al.; here the phenol is
isolated in modest yield (48%) after refluxing the aryl chloride in
aqueous NaOH [9].
involved the direct CeH oxidative of 1,8-naphthalimide using
ꢀ
MnO
2
, KOH and KOAc in the melt at 220 C [7]. The generality of this
In light of recent advancements in BuchwaldꢁHartwig type
palladium-mediated hydroxylation of arylhalides [10], we sought
to apply these approaches to directly convert the 4-chloro-1,8-
naphthalimides to the phenolic derivatives. This study sees the
*
Corresponding author.
E-mail address: t.ashton@deakin.edu.au (T.D. Ashton).
http://dx.doi.org/10.1016/j.dyepig.2015.11.007
143-7208/© 2015 Elsevier Ltd. All rights reserved.
0

C.L. Fleming et al. / Dyes and Pigments 126 (2016) 118e120
119
investigated as it is amenable to larger scales without specialised
reactors.
Treating 4-chloro-N-propyl-1,8-naphthalimide (6a, Table 1)
with Pd(OAc)
2
(2 mol%), t-BuXPhos (L1, 8 mol%) and K
2
CO
3
ꢀ
(3.0 equiv) in DMF/H
2
O (9:1) at 100 C led to consumption of the
starting material in 24 h. Dilution of the reaction mixture using
O and acidification using 2 M HCl gave an isolable precipitate,
with further purification giving the desired phenol 8a in 90% yield.
Me t-BuXPhos (L2) was also reported by Buchwald as a suitable
ligand for this transformation, using KOH and Pd (dba) [10a].
H
2
4
2
3
When L2 was used in place of t-BuXPhos (entry 2), only 9% con-
ꢀ
version to the phenol 8a was observed after 24 h at 100 C.
Interestingly, in this 2006 report, the use of inorganic bases
resulted in aryl ether formation; this by-product was not observed
in any examples presented here. Based on work from the Stra-
diotto group [10i], bippyphos (L3) was also investigated (entry 3);
Fig. 1. Examples of 4-hydroxy-1,8-naphthalimide based fluorescent probes.
ꢀ
here the reaction required 27 h at 100 C to achieve full conversion
and the product was isolated in good yield (88%). In keeping with
results from the Stradiotto report, electron deficient arenes
required elevated temperatures to achieve synthetically useful
conversion. Despite bippyphos (L3) presenting as a suitable
alternative we continued our study using t-BuXPhos (L1) due to
the relative expense of these biarylphosphines. Curiously, the 4-
bromo derivative 7 acted as a poor substrate with only 60% con-
development of conditions with functional group tolerance which
complement existing procedures and utilise relatively inexpensive
reagents.
2
. Results and discussion
ꢀ
version achieved after 48 h at 100 C (entry 4); whilst this is a
Hydroxylation conditions reported by Chern et al. were selected
as a starting point due to favourable factors such as (i) para-
counterintuitive result it only serves to support our preference for
the 4-chloro substrates. Control reactions were also performed in
substituted carbonyl functional groups were tolerated; (ii)
2
the absence of Pd(OAc) or ligand; these reactions failed to give
Pd(OAc)
2
exhibited comparable results to Herrmann's palladacycle,
any appreciable conversion to the phenol.
(
iii) and the t-BuXPhos ligand is reasonably affordable as a specialist
A number of functional groups tolerated the hydroxylation
conditions and the results are shown in Table 1. The hydroxyethyl
imide 6b was converted to the phenol product 8b in moderate yield
(entry 5, 50%), however this compares favourably Li's two-step
approach (35% over two steps) [4c]. When the alcohol is pro-
tected as a TBS-ether the yield of the 4-hydroxy product 6c was 61%
ꢀ
ligand [10h]. Following Chern's conditions (MW heating, 110 C,
0 min) there was evidence of product formation by TLC. However,
3
it was apparent that the inherent poor solubility of the naph-
thalimide was detrimental to the reaction. Despite the utility of
microwave assisted organic synthesis, conventional heating was
Table 1
Palladium-catalysed hydroxylation and substrate scope.
Entry
Substrate
X
R
Ligand
T (h)
Conv. (%)a
Product
Yield (%)
90
1
2
3
4
5
6
7
8
9
6a
6a
6a
7
6b
6c
6d
6e
6f
Cl
Cl
Cl
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
n-Pr
n-Pr
n-Pr
n-Pr
CH
CH
L1
L2
L3
L1
L1
L1
L1
L1
L1
L1
L1
24
24
27
48
48
48
24
20
24
24
24
100
10
100
60
100
100
100
100
100
100
0
8a
8a
8a
8a
8b
8c
8d
8e
8f
b
ND
88
ND
50
61
65
76
58
2
2
CH
CH
2
OH
OTBS
2
Allyl
(CH
(CH
Ph
2
)
)
5
C(O)OH
2
5
C(O)NHOTHP
c
1
1
0
1
6g
6h
8g
e
82
H
e
a
b
c
For reactions which were not complete after the indicated time using TLC, conversion was determined by 1H NMR spectroscopy after work-up.
ND ¼ Not determined.
2
DMF/H O (95:5) was used as the solvent system.

120
C.L. Fleming et al. / Dyes and Pigments 126 (2016) 118e120
(
entry 6), importantly, by carefully adjusting the pH during work up
Acknowledgements
the acid labile protecting group survived the process. An N-allyl
substituent also tolerated the reaction conditions and 8d was iso-
lated in 65% yield (entry 7). Hexanoic acid 8e (entry 8) and pro-
tected hydroxamic acid 8f (entry 9) were also successfully
synthesised (76 and 58% yield, respectively), this is encouraging as
some reactions involving longer alkyl imide substituents can be
problematic [11]. Once again an acid-labile protecting group (THP)
tolerated the reaction conditions and gives rise to precursors of
potential theranostic agents [12]. Finally, N-phenylimide 8g was
synthesised in very good yield (82%, entry 10) using the described
T.D.A and F. M.P. wish to thank the ARC (DP140100227) and the
Centre for Chemistry and Biotechnology for financial support. The
authors would also like to thank the Australian Research Council for
funding Deakin University's Nuclear Magnetic Resonance Facility
through LIEF grant LE110100141.
Appendix A. Supplementary data
conditions, although a higher ratio of DMF to H
required for substrate solubility. Similarly, the unsubstituted imide
g (entry 11) failed to give any hydroxylated derivative which we
2
O (95:5) was
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.dyepig.2015.11.007.
6
posit to a lack solubility.
The photophysical properties of the fluorophores in both DMSO
and physiologically relevant conditions (50 mM phosphate buffer,
pH 7.4) are outlined in Table S1. It is worth noting that we were
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2
Pd(OAc) /t-BuXPhos). The compounds generated are accompanied
with key photophysical properties.