Visible light-mediated Smiles rearrangements and annulations of non-activated aromatics

Article abstract of DOI:10.1039/d0cc04666c

We report the first examples of radical cation Smiles rearrangements. A series of aryloxy alkylamines underwent spontaneous reaction, with the amino group displacing theipso-alkoxy group through substitution, at ambient temperature and under photoactivation by visible light in the presence of an acridinium catalyst (5 mol%). The study was extended to 3-(2-methoxyphenyl)propan-1-amine derivatives, which lack an appropriateipsoleaving group. Here, efficient cyclisations resulted in displacement of the methoxy group and formation of tetrahydroquinolines.

Full text of DOI:10.1039/d0cc04666c

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DOI: 10.1039/D0CC04666C
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Visible Light-Mediated Smiles Rearrangements and Annulations of
Non-Activated Aromatics†
Connor A. Lawson,*a,b Andrew P. Dominey, a Glynn D. Williams, a,c and John A. Murphy*b
Received 00th June 2020,
Accepted 00th June 2020
DOI: 10.1039/x0xx00000x
We report the first examples of radical cation Smiles
rearrangements. series of aryloxy alkylamines underwent
A
spontaneous reaction, with the amino group displacing the
ipso-alkoxy group through substitution, at ambient temperature
and under photoactivation by visible light in the presence of an
acridinium catalyst (5 mol%). The study was extended to 3-(2-
methoxyphenyl)propan-1-amine derivatives, which lack an
appropriate ipso leaving group. Here, efficient cyclisations resulted
in displacement of the methoxy group and formation of
tetrahydroquinolines.
Development of complementary synthetic methods for the
preparation of arylated amines is of high importance, due to
their widespread presence in pharmaceuticals, natural products
and organic materials. Phenol derivatives have emerged as
attractive starting materials due to their abundance, and the
ability to derive them from renewable sources.1
Over the last decade, photoredox catalysis has become
immensely popular, through its role in engaging in efficient and
sustainable transformations.2,3 The exploitation of visible-light
has seen a vast number of methodologies developed that are of
great synthetic utility due to the mild conditions deployed to
heteroaromatic amines (Scheme 1a).8 Further expansion of
photocatalysed SNAr of anisoles has been reported by the
Nicewicz group.9,10
access highly reactive species.4
A
rising interest in
photochemistry has been seen from the pharmaceutical
industry.5
We proposed that these conditions could be adapted to
allow mild and efficient intramolecular reactions. The Smiles
rearrangement is an intramolecular SNAr reaction occurring at
the ipso position in an aromatic system.11 The Smiles
rearrangement is an important tool in synthetic chemistry, as
demonstrated by diverse advances described in the literature.12
Generally, Smiles rearrangements are often limited to electron-
poor arenes. Examples of thermally driven Smiles
rearrangements of non-activated aromatic systems are sparse
and typically require forcing conditions and harsh reagents over
prolonged reaction times (Scheme 1b).13
Organic photoredox catalysts are growing in popularity due
to the avoidance of expensive and toxic metals such as
ruthenium and iridium.6 Acridinium salts are among the most
popular of these.7 In 2017, Tay and Nicewicz described with
great success the use of acridinium salts to catalyse the
nucleophilic aromatic substitution (SNAr) of anisoles with N-
a. Chemical Development, GSK, Gunnels Wood Road, Stevenage, SG1 2NY, UK. E-
mail: connor.x.lawson@gsk.com.
Neutral radical versions of the Smiles rearrangement are
also known and have been established by the groups of
Speckamp and Motherwell.14 More recently developments by
Nevado15 and Stephenson16 are part of an increasing torrent of
b. Department of Pure and Applied Chemistry, University of Strathclyde, 295
Cathedral Street, Glasgow, G1 1XL, UK. E-mail: john.murphy@strath.ac.uk
c. Current Address: API Development, Aptuit (Oxford) Ltd, an Evotec Company, 111
Innovation Dr, Milton, Abingdon, OX14 4RZ, UK.
†Electronic Supplementary Information (ESI) available: Detailed experimental
procedures and characterisation data for new compounds. See
DOI: 10.1039/x0xx00000x
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radical-Smiles rearrangements reported in the literature, Employing TFE alone as solvent increased the obseVrivewedArsticoleluOtniolinne
including photochemical and electrochemical methods.17
yield to 92% (Entry 2). In related systems, the importance of
DOI: 10.1039/D0CC04666C
Inspired by recent developments in the Newman-Kwart fluorinated alcohols has been linked to their ability to hydrogen
rearrangement, where chemical, photochemical and bond key reaction intermediates.20 Changing to MeCN, a
electrochemical methods for single-electron oxidation solvent with a lower toxicity burden than TFE, proved
enhanced reactivity, we proposed a radical cation approach to unsuccessful (Entry 3, 2%). Moderate yields were observed
the Smiles rearrangement.18 We now show that a range of when another highly fluorinated alcohol solvent, 1,1,1,3,3,3-
aryloxy alkylamines successfully undergo a mild and efficient hexafluoro-2-propanol (HFIP), was employed (Entry 4, 42%). We
photo-Smiles rearrangement using an acridinium salt as the also found that these reactions work equally as efficiently if DCE
organophotoredox catalyst (Scheme 1c).
is replaced by α,α,α-trifluorotoluene (TFT) (see ESI, 86%).
To our knowledge, this approach yields the first examples of
Based on photophysical and electrochemical properties,
radical cation-promoted Smiles rearrangements. Our other commonly used organophotocatalysts were tested. 2,4,6-
publication at this stage is prompted by the very recent report Triphenylpyrylium tetrafluoroborate (TPT) (PC2) represents an
from the Nicewicz lab which details the use of primary example from an extremely powerful class of photo oxidants.21
alkylamine nucleophiles in intermolecular radical-cation However, a moderate solution yield of 29% was observed when
accelerated nucleophilic aromatic substitutions.10
PC2 was employed, possibly due to chemical instability (Entry
Our studies began with the evaluation of 2-phenoxyethan- 5).22 Dicyanoanthracene (DCA) (PC3) offers an attractive
1-amine (6a). Pleasingly, the reaction of 6a (0.4 mmol) with 9- catalyst alternative, owing to its structural simplicity and
mesityl-3,6-di-tert-butyl-10-phenylacridinium
greater commercial availability.23 Under our conditions, DCA
tetrafluoroborate (PC1) (5 mol%) in a 1:1 mixture of 2,2,2- displayed a promising solution yield of 15%, considering that it
trifluoroethanol (TFE) and 1,2-dichloroethane (DCE) under showed poor solubility in TFE (Entry 6). Two other acridinium
visible light irradiation with a general purpose 40 W blue LED salts were also tested as photocatalysts (see ESI). Both showed
lamp (see ESI for light source characterisation) in a nitrogen good reactivity with slightly diminished yields over PC1
,
atmosphere for 24 hours at ambient temperature gave the however, they have been reported in the literature as suffering
rearranged product 7a in 87% solution yield (Table 1, Entry 1).
from chemical instability3 and were pursued no further.
Once PC1 was established as the optimal catalyst, the
loading was adjusted. Organocatalysis has been criticised for its
inability to perform at low catalyst loadings.24 In our case,
decreasing the catalyst loading to 1 mol% (Entry 7, 92%) had no
effect on the reaction outcome. Moreover, no noticeable
change in yield was observed when catalyst loading was
increased to 10 mol% (Entry 8, 90%). Dilution of the reaction
mixture to 0.05 M showed an improved solution yield (96%)
(Entry 9 vs. Entry 2) and conversely, concentrating the reaction
to 0.2 M showed a drop in solution yield (Entry 10, 82%). For
convenience, 0.1 M was selected as the reaction concentration
on this scale for further studies. Control reactions indicated the
importance both catalyst and light had on the success of the
transformation. In the absence of catalyst, trace amounts of
product were observed (Entry 11). Heating the reaction mixture
Table 1 Optimisation of the reaction conditions.a
Solvent
[conc.]
Photocatalyst
PC (loading)
PC1 (5 mol%)
7a yield
(%)b
87
Entry
1
Variations
-
TFE:DCE (1:1)
[0.1 M]
2
3
4
5
6c
7
8
9
10
11
12d
TFE [0.1 M]
MeCN [0.1 M]
HFIP [0.1 M]
TFE [0.1 M]
TFE [0.1 M]
TFE [0.1 M]
TFE [0.1 M]
TFE [0.05 M]
TFE [0.2 M]
TFE [0.1 M]
TFE [0.1 M]
PC1 (5 mol%)
PC1 (5 mol%)
PC1 (5 mol%)
PC2 (5 mol%)
PC3 (5 mol%)
PC1 (1 mol%)
PC1 (10 mol%)
PC1 (5 mol%)
PC1 (5 mol%)
-
-
-
-
-
-
-
-
-
92
2
42
29
15
92
90
96
82
trace
0
-
-
PC1 (5 mol%)
dark/80 °C
a
Unless otherwise stated, all reactions were conducted using 0.4 mmol of 6a in
degassed solvent [0.1 M] and irradiated with a Kessil lamp (40 W, A160WE Tuna
b
Blue) for 24 h. Yields determined by 1H NMR analysis of the crude reaction
mixtures using 1,3,5-trimethoxybenzene as an internal standard. c Catalyst showed
poor solubility in solvent. d Reaction run at 80 °C. DCE = 1,2-dichloroethane; TFE =
2,2,2-trifluoroethanol; HFIP
=
1,1,1,3,3,3-hexafluoro-2-propanol. Catalyst
photophysical and electrochemical properties reported in literature.3,6,19
2 | J. Name., 2012, 00, 1-3
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to reflux in the dark with catalyst showed no product formation
(Entry 12).
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DOI: 10.1039/D0CC04666C
Following screening, a range of arenes was subjected to the
optimum conditions and the reaction products were
subsequently isolated (Scheme 2). The product 7a derived from
substrate 6a was isolated in 85% (1H NMR yield was 92%). para-
Alkyl substrates (6b–6d) were successfully rearranged and
products isolated respectively in 63%, 73% and 80% yield. The
success of isopropyl (6c) and tert-butyl (6d) substrates indicated
that sterically bulky groups around the arene impacted little on
the excited acridinium’s ability for single electron transfer (see
ESI for further discussion). A single rearranged product (7e) was
formed in good yield (74%) when ortho-methoxy derivative (6e
)
was subjected to the reaction conditions. No competing cyclised
product was observed as would arise from displacement of the
ortho-methoxy group, illustrating the faster kinetics of the ipso-
substitution. To answer the question whether ortho-
substitution would be possible in the absence of a Smiles
rearrangement, we prepared and tested appropriate substrates
(see below). Surprisingly, para-methoxy substrate (6f) showed
poor conversion to product (4% isolated after 65 h irradiation),
with unreacted starting material accounting for the remainder
of the mass balance (see ESI). Biphenyl derivative (6g) gave a
moderate yield of the desired Smiles product 7g (32%).
Propylene-linked substituent (6h) was smoothly rearranged to
the Smiles product (7h) in 83% yield, progressing via a 6-
membered cyclic transtion state. The rearrangement also
occurred with an electron-withdrawing fluoro present (6i) in
excellent yield (81%). However, a nitro-containing substituent
the efficient preparation of antibacterial imidazo[1,2-
a]quinoline 11f (80%).25
Anisole derivatives (ca. +1.8 V vs. SCE) and primary
alkylamines (+1.5 to +1.6 V vs. SCE) typically exhibit low
oxidation potentials.26 Therefore, it is possible under the
conditions employed (PC1, E*red = +2.15 V vs. SCE) that the
substrates undergo single electron oxidation at the amine or the
arene.8 In closely related systems, mechanistic probing has
suggested arene radical cations are key intermediates.8-10
However, other photoredox transformations involving
alkylamines have been proposed to progress via amine radical
cation pathways.27 Our proposed mechanism is shown below
(Scheme 5). Visible light excitation of the ground-state
acridinium salt (PC1) to an excited state (PC1a) enables the
oxidation of phenoxyalkylamine (6a) to an arene radical cation
(
6j, see ESI) showed no reactivity under our conditions.
We note in the current results of Nicewicz and Venditto that
(
6aa). The tethered primary amine subsequently adds to the
ipso- position, giving rise to Meisenheimer complex (6ab).
Proton transfer and reduction by the acridinyl radical (PC1b
secondary amines were not successful in intermolecular SNAr
reactions.10 Our preliminary investigations into the Smiles
rearrangement of secondary amines are noteworthy, showing
)
lead to the Smiles rearrangement product
(7a) and
modest initial success in converting challenging substrate (
product ( ) and demethylated product (7a) (Scheme 3). It is
likely that 7a arose from oxidative demethylation of 9 6
8) to
regeneration of the ground state catalyst (PC1).
9
.
Encouraged by the results of the ipso-substitutions seen
above, we now moved to explore ortho-substitutions (Scheme
4). 3-(2-Methoxyphenyl)propan-1-amine (10a) was prepared
and was successfully cyclised to form tetrahydroquinoline (11a
)
in a good yield (66%). Tolyl (10b) and biphenyl (10c) derivatives
were also cyclised in very good yields to provide the
corresponding tetrahydroquinoline derivatives (75% and 73%
respectively). Electron-rich dimethoxy derivative (10d) also
cyclised well following prolonged irradiation times (49%).
Finally, electron-poor carbomethoxy derivative (10e) afforded
desired product 11e in moderate yield (38%). Synthetic
applicability was extended to a medicinally relevant core with
This journal is © The Royal Society of Chemistry 20xx
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In conclusion, a range of primary aryloxylamines has been
successfully reacted in a novel radical cation promoted photo-
Smiles reaction using an acridinium salt as an
organophotocatalyst. The use of a single electron oxidant has
enabled efficient Smiles rearrangements of electron-rich
aromatics, that are typically inert and unreactive in this manner
in the ground state, leading to substituted anilines via radical
cation intermediates. Whereas these reactions show success in
ipso rearrangement, ortho cyclisations of appropriate
substrates to afford tetrahydroquinolines are also reported. We
are currently extending these studies.
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DOI: 10.1039/D0CC04666C
H
O
N
Acridinium Salt
466 nm LEDs
NH2
OH
BF4
R
n
R
n
tBu
N
tBu
• metal-free • mild conditions • high yields
• range of arenes demonstrated
Acridinium Salt
Photo-Smiles rearrangement of non-activated arenes
Novel and efficient visible light-mediated Smiles rearrangements and annulations progressing via a
radical-cation intermediate catalytically generated with acridinium salts.