Formal Bromine Atom Transfer Radical Addition of Nonactivated Bromoalkanes Using Photoredox Gold Catalysis

Article abstract of DOI:10.1021/acs.orglett.0c03030

Organic transformations mediated by photoredox catalysis have been at the forefront of reaction discovery. Recently, it has been demonstrated that binuclear Au(I) bisphosphine complexes, such as [Au2(μ-dppm)2]X2, are capable of mediating electron transfer to nonactivated bromoalkanes for the generation of a variety of alkyl radicals. The transfer reactions of bromine, derived from nonactivated bromoalkanes, are largely unknown. Therefore, we propose that unique metal-based mechanistic pathways are at play, as this binuclear gold catalyst has been known to produce Au(III) Lewis acid intermediates. The scope and proposed mechanistic overview for the formal bromine atom transfer reaction of nonactivated bromoalkanes mediated by photoredox Au(I) catalysis is presented. The methodology presented afforded good yields and a broad scope which include examples using bromoalkanes and iodoarenes.

Full text of DOI:10.1021/acs.orglett.0c03030

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Letter
Formal Bromine Atom Transfer Radical Addition of Nonactivated
Bromoalkanes Using Photoredox Gold Catalysis
Montserrat Zidan, Terry McCallum, Rowan Swann, and Louis Barriault*
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ABSTRACT: Organic transformations mediated by photoredox
catalysis have been at the forefront of reaction discovery. Recently,
it has been demonstrated that binuclear Au(I) bisphosphine
complexes, such as [Au2(μ-dppm)2]X2, are capable of mediating
electron transfer to nonactivated bromoalkanes for the generation
of a variety of alkyl radicals. The transfer reactions of bromine,
derived from nonactivated bromoalkanes, are largely unknown.
Therefore, we propose that unique metal-based mechanistic
pathways are at play, as this binuclear gold catalyst has been
known to produce Au(III) Lewis acid intermediates. The scope
and proposed mechanistic overview for the formal bromine atom
transfer reaction of nonactivated bromoalkanes mediated by
photoredox Au(I) catalysis is presented. The methodology presented afforded good yields and a broad scope which include
examples using bromoalkanes and iodoarenes.
hotoredox catalysis has been a growing field in synthetic
organic chemistry. Photochemistry combined with radical
require the use of disubstituted geminal olefins (R = Me and
R′ = H) to avoid β-hydride elimination products. Alexanian
and co-workers have reported palladium-catalyzed carbocycli-
zation of bromoalkanes.7 Although this method generates
mainly Heck type products, the formation of primary and
secondary (when R = H) bromocycloalkanes via a formal
bromine atom transfer radical addition (BrATRA) has been
observed in a few cases. Bromine transfer reactions from
nonactivated bromocycloalkanes remain largely undeveloped.
In this context, we report a photoredox BrATRA reaction using
dimeric gold complexes (Scheme 1C).8 This strategy would
also be waste limiting as a redox neutral reaction pathway
could be achieved by an oxidative quenching cycle, combined
with gold Lewis acid catalysis.9
Recently, we reported the homocoupling of alkyl radicals
generated from bromoalkanes through the reductive elimi-
nation of a putative Au(III) intermediate.10 Furthermore, the
unprecedented alkylative semipinacol rearrangement demon-
strated further evidence for the formation of Au(III)
intermediates and subsequent reductive elimination pro-
cesses.11,12 Looking to probe the Au(III) intermediates further,
we set out to investigate the elementary reaction more closely.
P
chemistry can perform photoinduced single-electron transfers
(PET or SET) and follow one-electron reaction pathways.1
The harnessing of both fields of chemistry synergistically
makes for a great match for accessing new chemical reactions.
While some traditional radical reactions require strong
oxidants and harsh conditions, photoredox chemistry allows
for the formation of new C−C bonds under mild conditions.2
Organic chemists now have new methods of functionalization
using transition metal or organic dye photosensitizers,
imitating what biomolecules can do in Nature, where photons
can be transformed into chemical energy.3 In 1945, Kharasch
and co-workers reported the first atom transfer radical addition
(ATRA) reaction, utilizing it in the difunctionalization of
alkenes.4 ATRA reactions became a great method to
functionalize unsaturated C−C bonds. The addition of
electrophilic radicals derived from α-bromoesters to relatively
nucleophilic alkenes became a great way to perform the
conventional ATRA reaction.5 To this end, these reactions
require harsh conditions and the need for radical initiators
(peroxides, or triethyl borane), and additives (organotin
reagents) as the reaction follows a radical chain-type
mechanism (Scheme 1A). Recently, intramolecular formal
ATRA reactions have been accomplished using transition
metals. The groups of Sanford and Lautens utilized Heck
reaction intermediates to perform carbohalogenation reactions
starting from iodoarenes and have expanded their method-
ology by using Pd- and Ni-based catalysts (Scheme 1B).6 In
most cases, metal-catalyzed carbohalogenation reactions
Received: September 10, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03030
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
Scheme 1. Previous and Present Work in Formal BrATRA
Reactions
Scheme 2. Proposed Mechanism
Initial experiments showed that irradiation of bromoalkane 1
in the presence of Au2(μ-dppm)2Cl2 (5 mol %) in MeCN/
H2O (7:3) gave a mixture of products 2a (56%), 3a (10%),
and 4 (14%) (Table 1, entry 1). It is important to note that we
Table 1. Optimization of Reaction Conditions
a
entry
X
[M]
time (min) 1a (%) yield (%) 2a/3a/4a
1
2
3
4
5
6
7
8
9
10
11
12
13
Cl
OTf
SbF6
BF4
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
0.067
0.067
0.067
0.067
0.067
0.067
0.067
0.067
0.033
0.033
0.033
0.033
0.033
180
180
180
180
180
180
10
10
10
10
10
0
0
5
5
4
58
0
29
0
56:10:14
53:2:0
49:5:7
26:1:0
61:4:5
22:5:0
80:3:8
43:11:6
82:3:8
82:16:0
0:0:0
b
c
During this time, products deriving from the formal BrATRA
were identified. Due to the unprecedented nature of the
peculiar reaction, it demanded a closer look.
d
c
0
Mechanistically, we hypothesized that this transformation
was mediated by the excitation of Au2(μ-dppm)2(NTf2)2
(*[AuI−AuI]) with UVA light followed by an oxidative
quenching event with bromoalkene (1) through an inner
sphere exciplex (bromoalkanes: E1/2red = ∼−2.5 V vs SCE and
e
100
100
100
f
10
10
0:0:0
0:0:0
g
a
b
1H NMR yield using mesitylene as internal standard. 2 mol % of the
c
catalyst was used. Deuterated solvents were used (MeCN-d3/D2O,
7:3). Reaction run in MeCN-d3. In the absence of Au2(μ-
dppm)2(NTf2)2. In the absence of UVA LED light in the presence
of photocatalyst. Heating to 80 °C with photocatalyst in the absence
of UVA LED irradiation.
red
*[Au2(μ-dppm)2]Cl2: E1/2 = −1.63 V vs SCE) as shown in
d
e
Scheme 2.13,15 The resulting free alkyl radical undergoes a 5-
exo-trig cyclization to form a 5-membered ring exocyclic radical
which can react further through path A or path B. Path A
proposes an unprecedented atom transfer radical addition
(BrATRA), where the alkyl radical abstracts a bromine atom
from an Au−Br species, giving the new bromoalkene and
regenerating the ground state of the gold catalyst. Path B
proposes the addition of the radical to the AuII center to form
an [AuI−AuIII−R] intermediate. This may also proceed via
alkyl radical addition to the AuI center, giving [R−AuII−AuII],
followed by reorganization to the [AuI−AuIII−R] intermedi-
ate.14 Reductive elimination of the alkyl group and the
bromide can form 2 and regenerate the ground state of the
catalyst. Alternatively, a chain reaction mechanism could be
considered, but this is unlikely since this process requires the
use of activated haloalkanes.15
f
g
previously reported the specific formation of compounds 3a
and 4a using the photoexcited [Au2(μ-dppm)2]Cl2 under
reductive quenching conditions.9,13b,f We found that the
variation in counterions had an effect on the reaction
performance; the reactions carried out with counterions such
as OTf and NTf2 provided better yields for the formation of 2a
than Cl, SbF6, and BF4 (entries 1−5). The best result was
observed using [Au2(μ-dppm)2][NTf2] (5 mol %), where 2a
was obtained in 61% yield along with trace amounts of 3a and
4a (entry 5).
B
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Lowering the catalyst loading did not improve the yield of
the reaction as only 42% conversion of 1a was observed (entry
6). Monitoring the reaction with NMR in deuterated solvent
revealed that the reaction was fully converted in 10 min
providing 2a in 80% yield with trace amounts of 3a and 4a
(entry 7). The reaction run in only MeCN-d3 led to poor
conversion and yields (entry 8). Lowering the concentration to
0.033 M did not affect the yield of the reaction (entry 9).
Using the same conditions but with nondeuterated solvents
showed a similar yield of 2a and a slight increase of 3a (16%;
likely due to hydrogen atom abstraction from the solvent), but
no 4a was observed (entry 10). Finally, control experiments
showed that the photocatalyst and light were needed to
perform the reaction (entries 11−13).
the compound patterns listed above are compatible with our
methodology. Having monosubstituted olefins and disubsti-
tuted terminal olefins was also compatible with our method-
ology (Scheme 3A). The cyclization of malonate-based
substrates 1a and 1b gave the desired compounds 2a and 2b
in 82% and 55% yields, respectively. In both cases, small
amounts of the reduced side products 3a (16%) and 3b (29%)
were observed. Moving onto the NTs-based substrates, the use
of monosubstituted alkenes 1c provided the desired product 2c
in 82% yield with trace amounts of its reduced counterpart
(>5%), while disubstituted olefins 1d gave bromocycloalkane
2d in 50% yield along with 3c (21%). These results suggest
that paths A or B are affected by steric hindrance leading to the
formation of competitive processes. Switching to allyl ethers
1e−i, the corresponding 5- and 6-membered rings 2e−i were
obtained in moderate to good yields. Volatile bromoalkanes
were also employed, and their results were recorded using
NMR spectroscopy (2j−2l). Using starting material 1j
provided a mixture of 1j and the desired product 2j (82%,
1:4 1j/2j). Furthermore, the opening of 1k and 1l was also
compatible with the methodology (Scheme 3B). Linear alkyl
bromides 2k and 2l were formed in good yields (72% and 55%
respectively). These results provide support for the formation
of free alkyl radicals in solution. Unfortunately, meaningful
data was not obtained when varying the concentrations of gold
catalyst, bromoalkane, or solution to obtain absolute rates for
the transformation using radical clocking methods. Given the
formation of 2k through a radical ring opening, we envisaged
an intermolecular photoredox cascade reaction between 1k and
cyclohex-2-enone. Under standard conditions, the desired
bicyclic compound 4 was obtained in 41% as a mixture of
diastereomer (1:1).
With optimized reaction conditions in hand, we explored the
reaction scope using allyl-functionalized NTs− and malonate-
tethered bromoalkanes as well as pyran- and furan-based
compounds (Scheme 3). The investigation showed that all of
Scheme 3. Intra- and Intermolecular Formal Bromine Atom
Transfer Radical Addition Reaction Scope
Next, we tested iodoarenes to see if similar reactivity to the
bromoalkanes could be achieved (Scheme 3C). It should be
noted that iodoalkanes are known to undergo chain reaction
mechanisms and as such, were excluded from this study. In
past methodologies, the use of iodoarenes resulted in products
from β-hydride elimination when not using a blocking group;
therefore, we were curious if our methodology was mild
enough to isolate the corresponding iodoalkanes. Starting with
O-tethered iodoarenes, the desired product was obtained in
good yields. Having a monosubstituted olefin 1m and
disubstituted olefin 1n gave the desired products 2m and 2n
in 62% and 45% yields, respectively. Nitrogen-based substrates
using Ac- and Ts- protecting groups were also compatible with
the methodology, giving the desired product in good yields.
Compared to other methods pertaining to this transformation,
the described protocol showed no need of a blocking group to
obtain the primary alkyl iodide.
The scope of the formal bromine transfer radical reaction
was extended to substituted alkenes (Scheme 4). Interestingly,
under the usual reaction conditions, the cyclization of alkene
1r led to the formation of the desired bicyclic bromide 2r in
29% (dr = 1:1) along with the elimination products 2r′ and
2r′′ in 54% yield (5:1). Similarly, the conversion of
trisubstituted 1s gave the desired product 2s in 41% yield
(dr = 2:1) along with the Heck-like compound 2s′’ in 58%
yield. However, the photoredox cyclization of nonterminal
olefin such as 1t led to the exclusive formation 2t and 2t′ in
75% yield as a mixture (2:1). This could be attributed to a fast
elimination of the tertiary bromine in the reaction medium.
In conclusion, we have developed a mild and operationally
simple intramolecular bromine atom transfer radical addition
a
Yields in parentheses correspond to the reduced product X = H.
b
c
Isolated yield at 1 mmol scale. NMR yield using mesitylene as
d
internal standard. 15 min reaction time.
C
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Letter
Notes
Scheme 4. Bromine Atom Radical Transfer Using
Substituted Alkenes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council (NSERC) and the University of Ottawa for support of
the described research. M.Z. thanks the government of Ontario
for an OGS M.Sc. scholarship and NSERC for Ph.D.
scholarship (PGS-D), and T.M. thanks NSERC for a Ph.D.
scholarship (CGS-D).
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03030.
General experimental procedures, detailed synthetic
procedures, and analytical data for all compounds
mentioned (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
Louis Barriault − Centre for Catalysis, Research and Innovation,
Department of Chemistry and Biomolecular Sciences, University
of Ottawa, Ottawa, Ontario K1N 6N5, Canada; orcid.org/
0000-0003-2382-5382; Email: lbarriau@uottawa.ca
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Authors
Montserrat Zidan − Centre for Catalysis, Research and
Innovation, Department of Chemistry and Biomolecular
Sciences, University of Ottawa, Ottawa, Ontario K1N 6N5,
Canada
Terry McCallum − Centre for Catalysis, Research and
Innovation, Department of Chemistry and Biomolecular
Sciences, University of Ottawa, Ottawa, Ontario K1N 6N5,
Canada
Rowan Swann − Centre for Catalysis, Research and Innovation,
Department of Chemistry and Biomolecular Sciences, University
of Ottawa, Ottawa, Ontario K1N 6N5, Canada
Complete contact information is available at:
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D
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