Alkene Carboarylation through Catalyst-Free, Visible Light-Mediated Smiles Rearrangement

Article abstract of DOI:10.1002/chem.201805712

A light-mediated Truce–Smiles arylative rearrangement is described that proceeds in the absence of any photocatalyst. The protocol creates two C?C bonds from simple starting materials, with the installation of an aryl ring and a difluoroacetate moiety across unactivated alkenes. The reaction proceeds via a radical mechanism, utilizing a light-mediated reduction of ethyl bromodifluoroacetate by N,N,N′,N′-tetramethylethylenediamine (TMEDA) to set up intermolecular addition to an unactivated alkene, followed by Truce–Smiles rearrangement.

Full text of DOI:10.1002/chem.201805712

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Accepted Article
Title: Alkene Carboarylation via Catalyst-Free, Visible Light-Mediated
Smiles Rearrangement.
Authors: David Whalley, Hung Duong, and Michael Greaney
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To be cited as: Chem. Eur. J. 10.1002/chem.201805712
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Alkene Carboarylation via Catalyst-Free, Visible Light-Mediated
Smiles Rearrangement.
David M. Whalley, Hung A. Duong,* and Michael F. Greaney*
Abstract: A light-mediated Truce-Smiles arylative rearrangement is
described that proceeds in the absence of any photocatalyst. The
protocol creates two C-C bonds from simple starting materials, with
the installation of an aryl ring and a difluoroacetate moiety across
intermolecular aminoarylation reaction that uses desulfonylative
Smiles chemistry catalyzed by an iridium complex and visible
light.8d
Encouraged by these works, along with our own experience in
unactivated alkenes. The reaction proceeds via a radical mechanism, developing photoredox catalysis reactions, 9 we planned the
utilizing a light mediated reduction of ethyl bromodifluoroacetate by
N,N,N′,N′-tetramethylethylenediamine (TMEDA) to set up
sequence set out in Scheme 1C. We envisaged a reaction
whereby a photocatalyst could undergo oxidative quenching by
ethyl bromodifluoroacetate 6 (Ered = −0.57 V vs SCE)10 to yield
an electrophilic radical species that could undergo addition to an
unactivated alkene such as 7 bearing a sulfonamide residue.
intermolecular addition to an unactivated alkene, followed by Truce-
Smiles rearrangement.
The bromodifluoroacetate moiety provides a stable radical that
The
Truce-Smiles
rearrangement
is
a
powerful
11
has been widely exploited in photoredox catalysis,
and
transformation in arene chemistry, involving the migration of aryl
rings via ipso-substitution.1 By cleaving easily formed C-X bonds,
and creating arene C-C bonds, it can convert readily available,
simple starting materials to higher-value functionalized arene
products. The desulfonylative Truce-Smiles, in particular, has
seen extensive application in recent years, exploiting tractable
sulfonamide and sulfonates as starting materials and extrusion
of SO2 to irreversibly drive the reaction. Both polar and radical-
variants are well established, with the radical reaction featuring
particularly strong substrate scope around the migrating aryl
moiety. Seminal work by Speckamp and Motherwell2 in this area
(Scheme 1A) established the reaction for purely intramolecular
introduces a valuable gem-difluoro group into the reaction
products. The resulting secondary alkyl radical 8 is then in a 1,5-
relationship to the ipso position on the aryl ring, allowing Truce-
Smiles rearrangement to take place. With the use of a tertiary
amine, the catalytic cycle could be completed via SET reduction
of the oxidized catalyst as well as providing a hydrogen atom
source to reduce the resulting N-centered radical in the product
molecule. Important precedent from Zard and coworkers12 has
demonstrated successful 1,5-aryl migration from a closely
related radical intermediate to 8, generated from a xanthate
precursor, suggesting that the Smiles process would be viable if
the right PRC-conditions could be found to mediate the overall
transformation.13
sp2 and sp3 carbon-centered radical systems, and the reaction
3
has since been widely exploited.
A
powerful recent
development is to embed the Truce-Smiles in a cascade
process, where the key radical intermediate is generated from a
precursor bond-forming event e.g. Scheme 1B from Nevado and
co-workers, 4 where the Michael acceptor 3 can undergo a
variety of intermolecular radical additions, setting up the radical
Smiles to construct sophisticated heterocyclic scaffolds.
Our recent work on tandem Smiles chemistry in the polar
regime5 encouraged us to examine a radical variant, with the
explicit aim of developing a photoredox process using visible
light. Photoredox catalysis enables radical generation under mild
reaction conditions, 6 using operationally simple, user-friendly
reaction set-ups. Novel photoredox Smiles processes have
recently been reported in the literature, with Brachet, Belmont
and co-workers describing
a phthalazine synthesis from
alkynylsulfonohydrazone rearrangement,7 and Stephenson and
co-workers developing desulfonylative and C-N cleaving Smiles
8
rearrangements
using ruthenium and iridium catalysis,
respectively. Recently, the Stephenson group have described a
[
[
]
]
*
*
D. M. Whalley, Prof M. F. Greaney
School of Chemistry, The University of Manchester
Oxford Road, Manchester, M13 9PL (UK)
E-mail: michael.greaney@manchester.ac.uk
Hung A. Duong
Scheme 1. Truce-Smiles rearrangement methodologies and reaction plan.
Institute of Chemical and Engineering Sciences (ICES), Agency for
Science, Technology and Research (A*STAR), 8 Biomedical Grove,
Neuros, #07-01, Singapore 138665, Republic of Singapore
duong_hung@ices.a-star.edu.sg
PRC = photoredox catalyst.
Our studies began with N-allyl-N-(arylsulfonyl)acetamide 7a as
the alkene acceptor, ethyl bromodifluoroacetate 6 and the
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201805712
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archetypal iridium catalyst fac-Ir(ppy)3 with N,N,N′,N′-
transformation provides a safe and cost effective method for
installing geminal difluoro groups on to an organic scaffold, and
we could switch the ester group to a phenylamide without a
problem (10).
We were pleased to observe successful reaction for a homoallyl
sulfonamide substrate, producing the hexyl product 11 in
moderate yield. The 1,5-Smiles process here proceeds through
a six-membered transition state, offering a counterpoint to the
1,4-reaction which dominates radical Smiles chemistry in the
literature.15
tetramethylethylenediamine
(TMEDA)
as
stoichiometric
reductant. We were pleased to isolate product 9a in an
encouraging 42% yield at room temperature under these
conditions, using DCM as solvent. Efforts then turned towards
developing the protocol to encompass more sustainable, cost
effective photocatalysts such as eosin Y and a copper complex
pioneered by Collins and coworkers.14 Both systems returned
moderate yields of product with dichloromethane as a solvent at
room temperature, however, switching to a higher boiling point
solvent and increasing the reaction temperature aided the
reaction (entry 6). In the course of conducting control
experiments, we were surprised to find that the reaction could
proceed without any photoredox catalyst, heating to 80 °C in
DMSO (Table 1, entry 7). This introduced the exciting possibility
of developing a visible light photochemical Smiles process with
no requirement for any photoredox catalyst. Further control
experiments established that the catalyst-free reaction
proceeded slowly at room temperature, and that there was no
reactivity in the dark (Table 1, entries 8 and 9).
Table 1. Optimization of the Truce-Smiles Rearrangement via radical addition
Entry
Catalyst[c]
Light Source
Reaction
Solvent
Yield
Temperature
Scheme 2. Reactions conducted on 0.1 mmol scale. [a] 59% for 1 mmol scale.
[b] Using 2-bromo-2,2-difluoro-N-phenylacetamide in place of 6. [c] N-(but-3-
en-1-yl)-N-(phenylsulfonyl)acetamide used in place of 7e
1[a]
2
A
B
C
C
B
B
-
Blue LEDs
Blue LEDs
Green LEDs
Green LEDs
Blue LEDs
Blue LEDs
Blue LEDs
Blue LEDs
-
r.t.
r.t.
DCM[d]
DCM[d]
42%[g]
40%[g]
46%[g]
49%[g]
39%[h]
59%[g]
67%[g]
26%[h]
0%[h]
3
r.t.
DCM[e]
Ethyl difluorobromoacetate 6 has been widely employed in
intermolecular difluoroalkylation reactions using ruthenium and
iridium photoredox catalysis (usually in the presence of an
inorganic base).11 Likewise, its facility as a fluoroalkyl radical
precursor in SRN1 processes is well-known,16 but with the usual
requirement for metal salts to promote the initial electron transfer
event. However, a number of visible light photochemical metal-
free systems have recently being reported17 for 6 and related
haloalkanes that use tertiary amine donors as reductants. To
elucidate how the ethyl bromodifluoroacetate starting material
could be reduced in our process we studied its interaction with
TMEDA by 19F NMR (Table 2). First, a mixture of 6 and TMEDA
in DMSO-d6 at ambient temperature in the dark was observed to
yield no reduced product. Second, heating the two compounds
to 80 ºC also gave no reduced product, supporting the results in
table 1 that the reaction is not initiated thermally. However, when
the two components were irradiated by blue LEDs for 15 hours,
97% conversion to ethyl difluoroacetate is observed.
Furthermore, when a solution of 6 was irradiated in the absence
of TMEDA, no reduced product was observed. UV/Vis
spectroscopy revealed that upon mixing these two components,
the UV/Vis absorbance is increased, particularly in the near UV
region, accompanied by a bathochromic shift (Figure 1). It is
therefore likely that TMEDA and 6 form an electron-donor
complex in solution, whereby an electron transfer event can be
triggered by the near-UV/shorter wavelengths of blue visible light
typically used in photoredox experiments.18 Finally, when the
reaction (conditions as Table 1, entry 7) was subjected to three
4
r.t.
DCM[e]
5
r.t.
DMSO[e]
DMSO[e]
DMSO[f]
DMSO[f]
DMSO[f]
6
80 ºC
80 ºC
r.t.
7[b]
8[b]
9[b]
-
-
80 ºC
Ts = toluenesulfonyl. r.t. = room temperature. Reactions conducted on a 0.1
mmol scale. [a] 15 h reaction time. [b] 2 equiv of 6. [c] A = fac-Ir(ppy)3 (1
mol%),
B
=
Cu(BINAP)(dq)BF4
3
mol%
(BINAP
=
(2,2′-
bis(diphenylphosphino)-1,1′-binaphthyl) dq = 2,2’-biquinoline) C = Eosin Y 3
mol%. [d] 0.10 M concentration. [e] 0.033 M concentration. [f] 0.040 M
concentration. [g] isolated yield. [h] Determined by 1H NMR using 1,3,5-
trimethoxybenzene as a standard.
With this catalyst free protocol in hand, we turned to examining
the scope of this reaction. Our previous reports of polar Truce-
Smiles rearrangements required electron poor aryl and
heteroaryl systems to stabilize the anionic Meisenheimer
intermediate. Here, however, we expected the radical system to
be free of this restriction and able to incorporate a larger variety
of aryl substituents. This proved to be the case, with a variety of
electron rich (7a – 7d), neutral (7e), and poor (7f – 7l) aryl
systems undergoing a smooth tandem reaction to yield the
products 9. The ethyl bromodifluoroacetate used in the
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equivalents of TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl,
the reaction failed to yield 10a, supporting the postulated radical
character of the mechanism.
Conditions
Conversion to 12
TMEDA, DMSO-d6, rt, dark, 15 h
TMEDA, DMSO-d6, 80 °C, dark, 15 h
TMEDA, DMSO-d6, rt, Blue LEDs, 15 h
0
0
97%
Table 2. Reduction of ethyl bromodifluoroacetate. Reaction conditions: 0.5 mL
of DMSO-d6, 0.15 mmol of 6, 0.30 mmol of TMEDA.
Scheme 3. Proposed mechanism for the Truce Smiles via radical addition
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Figure 1. UV/Vis study. 0.3 M concentration solutions in DMSO
Based on these results, we propose the pathway in Scheme
3 for the reaction, beginning with TMEDA photoreduction of
bromodifluoroacetate 6 to the radical 13. Intermolecular addition
gives the alkyl radical 8, which can undergo Truce-Smiles aryl
shift with extrusion of SO2. The resultant amidyl radical 14 can
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protocol that uses blue light and simple TMEDA as an electron
donor to promote a Truce Smiles cascade process. The reaction
exploits the ready availability of sulfonamide aryl groups,
transforming them to valuable C-arylated products, and is free
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We would like to thank the School of Chemistry (University of
Manchester) and A*STAR Singapore for funding, and Dr Daniele
Leonori (University of Manchester) for valuable discussions.
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Keywords: rearrangement
reactions
• photochemistry • radical
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Entry for the Table of Contents (Please choose one layout)
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David M. Whalley, Hung A. Duong,* and
Michael F. Greaney*
Page No. – Page No.
Alkene Carboarylation via Catalyst-
Free, Visible Light-Mediated Smiles
Rearrangement.
Light up a Smile. A visible light-mediated Truce-Smiles arylative rearrangement is
described that proceeds in the absence of any photocatalyst. The protocol creates
two C-C bonds from simple starting materials, adding an aryl ring and a
difluoroacetate moiety across an unactivated alkene.
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