A Cu-Catalysed Radical Cross-Dehydrogenative Coupling Approach to Acridanes and Related Heterocycles

Article abstract of DOI:10.1002/ejoc.201601336

The synthesis of acridanes and related compounds through a Cu-catalysed radical cross-dehydrogenative coupling of simple 2-[2-(arylamino)aryl]malonates is reported. This method can be further streamlined to a one-pot protocol involving the in situ fomation of the 2-[2-(arylamino)aryl]malonate by α-arylation of diethyl malonate with 2-bromodiarylamines under Pd catalysis, followed by Cu-catalysed cyclisation.

Full text of DOI:10.1002/ejoc.201601336

A Journal of
Accepted Article
Title: A Cu-Catalysed Radical Cross-Dehydrogenative Coupling
Approach to Acridanes and Related Heterocycles
Authors: Timothy Hurst and Richard Taylor
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10.1002/ejoc.201601336
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A Cu-Catalysed Radical Cross-Dehydrogenative Coupling
Approach to Acridanes and Related Heterocycles
Timothy E. Hurst*[a] and Richard J. K. Taylor*[a]
Abstract: The synthesis of acridanes and related compounds via
the Cu-catalysed radical cross-dehydrogenative coupling of simple
2-[2-(arylamino)aryl]malonates is reported. This method can be
further streamlined to a one-pot protocol involving the in situ
fomation of the 2-[2-(arylamino)aryl]malonate by α-arylation of
diethyl malonate with a 2-bromodiarylamine under Pd-catalysis,
followed by the subsequent Cu-catalysed cyclisation.
Introduction
Figure 1. Examples demonstrating the utility of acridanes.
In recent years C-H activation has emerged as a powerful and
attractive method in organic synthesis since it enables the
formation of C-C bonds without pre-functionalisation of one or
Given the proven utility of acridanes, the sparse number of
both of the coupling partners, thus leading to more efficient and
atom-economical processes. Within the wider pantheon of C-H
activation, cross-dehydrogenative couplings (CDC) have proved
to be versatile procedures for the selective formation of C-C
bonds from two different C-H systems under oxidative
conditions.[1] Our contribution in this area involves the synthesis
of diverse nitrogen heterocycles via the Cu-catalysed oxidative
coupling of Csp2-H/Csp3-H bonds;[2] a radical variant of the CDC
processs.
general methods available for their preparation is surprising.[3]
Traditionally, they have been prepared by nucleophilic addition
to existing acridines 4 or acridinium salts 5 (Scheme 1, eqn 1),[16]
or by a Friedel-Crafts type cyclisation of diarylamines 7 with
strong acid (Scheme 1, eqn 2).[17] However, the need to rely
either on the commercial availability or potentially lengthy
synthesis of acridines 4, coupled with the requirements for the
use of strong acids and well known problems of site-selectivity
associated with Friedel-Crafts cyclisations, means that new
approaches to highly substituted acridane derivatives are of
considerable interest.
9,10-Dihydroacridines (acridanes) have garnered much
attention[3] due to their potent biological activity, including
inhibition of class IIa histone deacetylase[4] and HIV reverse
transcriptase,[5] neuroleptic activity,[6] and as activators of K2P
potassium channels7 (e.g. 1, Figure 1). Furthermore, acridanes
have been employed as chemiluminescent sensors in
immunoassays[8] (e.g. 2), as NADH analogues in hydride-
transfer reactions,[9] as host materials in OLEDs[10] (e.g. 3), as
photoswitches,[11] and as molecular motors.[12] Moreover,
acridanes are valuable building blocks being readily oxidised to
acridines and acridones,[13] functionalised by C-H activation,[14]
and easily converted into 5H-dibenzo[b,f]azepines and 5,11-
dihydro-10H-dibenzo[b,e][1,4]diazepines via ring expansion.[15]
Thus, in continuation of our studies on the synthesis of
diverse heterocyclic scaffolds via the oxidative cyclisation of
linear precursors using inexpensive copper salts,[2] our goal was
to exploit this simple yet powerful methodology in the
preparation of
acridane
derivatives
10
from
2-[2-
(arylamino)aryl]malonates 9 (Scheme 1, eqn 3).
[a]
T. E. Hurst, R. J. K. Taylor
Department of Chemistry
University of York
Heslington, York, YO10 5DD, UK
E-mail: richard.taylor@york.ac.uk
http://www.york.ac.uk/chemistry/staff/academic/t-z/rtaylor/
Supporting information for this article is given via a link at the end of
the document.
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In the event, N-aryloxindoles 11 proved to be versatile
starting materials for the preparation of cyclisation precursors 15
via a 3 step protocol (Scheme 2). First, ring-opening of the
lactam moiety was carried out by treatment with NaOH in
refluxing THF, followed by in situ formation of the dianions 12 by
addition of n-BuLi at low temperature and subsequent trapping
with the appropriate electrophile to give carboxylic acids 13.[18]
Then, simple esterification, deprotonation with LiHMDS and
trapping with the requisite cyano- or chloroformate delivered 2-
[2-(arylamino)aryl]malonates 15a-j. In this manner, control over
the substitution pattern on the aromatic rings, as well at the
nitrogen atom and ester functionality could be readily achieved
(14–63% unoptimised overall yields; see SI for details).
Scheme 1. Approaches for the synthesis of acridanes.
The likely mechanism for this process, by analogy with
earlier studies,[2d,2f] is shown in Scheme 1. Initially, proton
abstraction and single electron oxidation would give malonyl
radical A, which would undergo intramolecular homolytic
aromatic substitution to give B, followed by further oxidation to
give the cyclohexadienyl cation C, which would finally aromatise
to generate the desired product 10. Evidence for a radical
based mechanism in these copper-mediated oxidative coupling
reactions includes radical clock experiments,[2d] as well as DFT
calculations conducted by Kündig in related systems.[2f] Clearly,
two equivalents of copper salt are nominally required to effect
both single electron oxidations involved in the process. However,
in related studies we have demonstrated that a catalytic amount
of the copper salt may be used with air serving as the terminal
oxidant.[2a-d]
Scheme 2. Modular synthesis of cyclisation precursors 15a-j.
With ready access to the required linear substrates established,
the cyclisation of model substrate 15a was then examined.
Pleasingly, treatment of 15a under the conditions previously
reported[2b] in our synthesis of oxindoles [Cu(2-ethylhexanoate)2
(10 mol%), toluene, reflux, open flask] delivered the desired
acridane 16a in 87% yield without the need for further
optimisation (Scheme 3). It is also noteworthy that the oxidative
coupling could be performed in the presence of only 5 mol% or 2
mol% of the catalyst, with only a minor drop in yield (Scheme 3,
footnote a).
Results and Discussion
Following this successful initial result, the generality of this
new copper-catalysed approach to acridanes was explored
(Scheme 3). First, cyclisation of 15b, bearing a removable
protecting group on nitrogen, was carried out to give N-
benzylacridane 16b, albeit in reduced yield compared to N-ethyl
derivative 16a. Next, acridanes 16c-f bearing differentially
The initial task was to develop a flexible and modular approach
for the synthesis of linear precursors 15 (Scheme 2) which
would allow the facile introduction of substituents at various
positions around the acridane skeleton.
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protected esters (e.g. allyl, Bn, Fmoc) were prepared, thus
opening the possibility for further manipulation of the cyclised
products (vide infra). The Fmoc-protected ester 16e was
crystalline, allowing unambiguous confirmation of its structure
through X-ray crystallographic analysis (see SI).
Next, the introduction of substituents at various positions on
either aromatic ring of the acridane skeleton was explored, with
16g-j obtained in good to excellent yields. Incorporation of a
nitrogen atom into one of the aromatic rings was also possible,
leading to isolation of the corresponding aza-acridane 16k in
66% yield.
Having established the effectiveness of the copper-catalysed
route to acridanes 16a-k, this method was extended to the
synthesis of other related heterocycles of interest, such as
xanthenes and thioxanthenes (Scheme 3, last two entries).
However, cyclisation of a linear diaryl ether in the presence of 10
mol% Cu(2-ethylhexanoate)2 under the standard reaction
conditions delivered xanthene 16l in a disappointing 33% yield.
Also isolated was an equal amount of a by-product identified as
ethyl 2-oxo-2-(2-phenoxyphenyl)acetate, which arises from
competing decarboxylation and aerial oxidation of the starting
material. This problem was exacerbated in the case of
thioxanthene 16m, which was isolated in only 20% yield along
with 53% of the undesired by-product. Further optimisation of
these latter processes is clearly required but fortunately, in both
cases, the yield of the oxidation by-products could be minimised
by performing the cyclisation under an atmosphere of argon,
leading to formation of xanthene 16l and thioxanthene 16m in
47% and 44% yields, respectively. While formation of the
desired products 16l and 16m is enhanced under these
conditions, performing the reaction under argon necessitates the
use of 2.5 equivalents of copper salt to allow the reaction to
proceed to completion (see proposed mechanism, Scheme 1)
Scheme 3. Scope of the Cu-catalysed synthesis of acridanes. [a] 16a was
obtained in 83% and 84% yield when Cu(2-ethylhexanoate)2 (5 mol% and 2
mol%) were used, respectively. [b] Cu(2-ethylhexanoate)2 (2.5 equiv) and
DIPEA (2.5 equiv) were used under an atmosphere of argon.
In order to demonstrate the utility of the acridanes derived from
the copper-catalysed cyclisation, a brief study on their further
functionalisation was carried out (Scheme 4). For example,
treatment of 16a with an excess of KOH in EtOH/H2O resulted in
saponification and decarboxylation to give acid 17 in excellent
yield, thus providing an alternative route which may be of use in
the synthesis of analogues of chemiluminescent sensors such
as 2 (Figure 1). Reduction of the esters was also achieved in
the presence of LiAlH4 to give diol 18 in 94% yield. Furthermore,
selective functionalisation of the allyl ester in 16c was carried
out by decarboxylative allylic alkylation on treatment with 4
mol% Pd(PPh3)4 to give 19, thereby generating
a new
quaternary carbon centre, again in excellent yield. Finally,
hydrogenolysis of the benzyl protecting group in 16b delivered
acridane 20 bearing a free N-H group in reasonable, un-
optimised yield.
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COMMUNICATION
picolinic acid19a (Table 1, entries 1-2). Similarly, other copper-
based catalyst systems reported[19b-d] for the coupling of dialkyl
malonates with simple haloarenes proved equally ineffective
(results not shown). Thus, attention turned to the use of
palladium catalysts to effect the initial transformation.
Table 1. Optimisation of the α-arylation of 21a-b with diethyl malonate.
Scheme 4. Further derivatisation of acridanes obtained from oxidative
coupling.
Entry
1
X
I
Conditions
Yield
[a]
CuI (10 mol%), 2-picolinic acid (20 mol%)
Cs2CO3 (3 equiv), dioxane, reflux, 17 h
–
In a final aspect to this work, we explored the potential of an
expedited, one-pot approach to acridanes 16 based on the α-
arylation of 1,3-dicarbonyl compounds with haloarenes 21
generating intermediates 15 in situ which would then undergo
the oxidative coupling procedure (Scheme 5). Given the well-
[a]
2
3
4
5
6
7
Br
I
CuI (10 mol%), 2-picolinic acid (20 mol%)
Cs2CO3 (3 equiv), dioxane, reflux, 17 h
–
Pd(OAc)2 (2 mol%), tBuMePhos (4.4 mol%)
K3PO4 (2.4 equiv), toluene, reflux, 18 h
–
[a]
known ability of copper salts to catalyse both processes,[19]
highly efficient transformation seemed attainable.
a
Br
I
Pd(OAc)2 (2 mol%), tBuMePhos (4.4 mol%)
K3PO4 (2.4 equiv), toluene, reflux, 18 h
–
[a]
Pd2dba3·CHCl3 (1 mol%), tBu3P·HBF4 (4 mol%)
K3PO4 (3 equiv), toluene, 70 °C, 15 h
32%
61%
72%
I
Pd2dba3·CHCl3 (1 mol%), tBu3P·HBF4 (4 mol%)
K3PO4 (3 equiv), toluene, reflux, 14 h
Br
Pd2dba3·CHCl3 (1 mol%), tBu3P·HBF4 (4 mol%)
K3PO4 (3 equiv), toluene, reflux, 17 h
[a] Starting materials only were observed by 1H NMR analysis of the
unpurified reaction mixture.
Scheme 5. Retrosynthesis of acridanes 16 via
arylation/cyclisation process.
a
one-pot α-
No α-arylation was observed using the Pd(OAc)2/t-
BuMePhos catalyst system developed by Buchwald (Table 1,
entries 3-4),[21] but an encouraging 32% yield of 15n was
obtained on switching to Pd2dba3·CHCl3 (1 mol%) as the catalyst
The requisite 2-halodiarylamines 21 were easily prepared by
the addition of commercially available 2-haloanilines 22 to
benzynes prepared in situ from 2-(trimethylsilyl)phenyl triflates
23 in the presence of CsF, then subsequent N-alkylation
(Scheme 6; see SI for more details).[20]
t
with the bench stable ligand Bu3P·HBF4 (4 mol%) in toluene at
70 °C (Table 1, entry 5).[22] Increasing the reaction temperature
allowed us to isolate 2-[2-(arylamino)aryl]malonate 15n in 61%
(from 21a) and 72% (from 21b) yields, respectively.
With conditions for the malonate coupling in hand, attention then
turned to establishing the one-pot α-arylation/cyclisation protocol
to prepare acridanes directly (Scheme 7). To this end, the Pd-
catalysed α-arylation reaction between 2-bromo-N-methyl-N-
phenylaniline 21b and diethyl malonate was first carried out
using the optimised conditions described above under an
atmosphere of argon. Subsequently, the reaction flask was
simply opened to the air, Cu(2-ethylhexanoate)2 (15 mol%) was
added, and heating continued for a further 24 h to facilitate the
cyclisation. In this manner, the target acridane 16n was isolated
in a pleasing 74% overall yield over the 2 steps. Furthermore,
substituents could be readily introduced on one, or both,
aromatic rings, allowing access to more highly substituted
Scheme 6. Synthesis of 2-halodiarylamines 21a-d.
Next, the crucial transition-metal catalysed α-arylation reaction
between diethyl malonate and 2-halodiarylamines 21a-b was
examined, selected results of which are shown in Table 1. In
the event, none of the desired α-arylation product was observed
on heating either 2-iodo- or 2-bromo-N-methyl-N-phenylaniline
21a-b with diethyl malonate in the presence of CuI and 2-
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acridanes such as 16o and 16p using this efficient one-pot
procedure.
Acknowledgements
We thank the Engineering and Physical Sciences Research
Council for postdoctoral funding (T.E.H.; EP/J000124/1) and Dr
A. C. Whitwood (University of York) for assistance with X-ray
crystallography.
Keywords: acridanes • copper • catalysis • cross-
dehydrogenative coupling • one-pot
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In summary, we report
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heterocycles from readily available 2-[2-
a
Cu-catalysed radical cross-
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uses inexpensive Cu(2-ethylhexanoate)2 as the catalyst under
mild conditions, thus avoiding many of the problems associated
with existing classical strategies for the synthesis of acridanes.
The diester moiety resulting from the oxidative coupling reaction
serves as a useful handle for further functionalisation. In addition,
we have established a streamlined protocol involving the in situ
formation of the cyclisation precursor by the α-arylation of diethyl
[9]
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a
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Experimental Section
Representative procedure for the copper-catalysed synthesis of
acridanes: To a solution of the cyclisation precursor 15 (1.00 mmol) in
toluene (10 mL) was added copper(II) 2-ethylhexanoate (35.0 mg, 0.100
mmol). The reaction mixture was heated at reflux (oil bath at 120 °C) for
17 h with the condenser left open to the air. After cooling to rt, saturated
NH4Cl (25 mL) was added and the aqueous phase extracted with EtOAc
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mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification
by flash column chromatography, eluting with EtOAc/hexane, afforded
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European Journal of Organic Chemistry
COMMUNICATION
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Copper Catalysis
Timothy E. Hurst* and Richard J. K.
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A Cu-Catalysed Radical Cross-
Dehydrogenative Coupling Approach
to Acridanes and Related
Heterocycles
The synthesis of acridanes and related compounds via the Cu-catalysed oxidative
cyclisation of simple linear precursors is described. A one-pot protocol involving α-
arylation of diethyl malonate with a 2-bromodiarylamine under Pd-catalysis,
followed by the subsequent Cu-catalysed cyclisation is also demonstrated.
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