Visible light-mediated atom transfer radical addition via oxidative and reductive quenching of photocatalysts

Article abstract of DOI:10.1021/ja300798k

Herein, the development of visible light-mediated atom transfer radical addition (ATRA) of haloalkanes onto alkenes and alkynes using the reductive and oxidative quenching of [Ir{dF(CF₃)ppy}₂(dtbbpy)]PF ₆ and [Ru(bpy)₃]Cl₂ is presented. Initial investigations indicated that the oxidative quenching of photocatalysts could effectively be utilized for ATRA, and since that report, the protocol has been expanded by broadening the scope of the reaction in terms of the photocatalysts, substrates, and solvents. In addition, further modifications of the reaction conditions allowed for the efficient ATRA of perfluoroalkyl iodides onto alkenes and alkynes utilizing the reductive quenching cycle of [Ru(bpy) ₃]Cl₂ with sodium ascorbate as the sacrificial electron donor. These results signify the complementary nature of the oxidative and reductive quenching pathways of photocatalysts and the ability to predictably direct reaction outcome through modification of the reaction conditions.

Full text of DOI:10.1021/ja300798k

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Article
Visible Light-mediated Atom Transfer Radical Addition
via Oxidative and Reductive Quenching of Photocatalysts
Carl-Johan Wallentin, John Duy Nguyen, Peter Finkbeiner, and Corey Robert John Stephenson
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja300798k • Publication Date (Web): 09 Apr 2012
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Journal of the American Chemical Society
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Visible Light-Mediated Atom Transfer Radical Addition via
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Oxidative and Reductive Quenching of Photocatalysts
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Carl-Johan Wallentin, John D. Nguyen, Peter Finkbeiner, Corey R. J. Stephenson*
Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States
Supporting Information Placeholder
ABSTRACT: Herein, the development of visible light-mediated atom transfer radical addition (ATRA) of haloalkanes onto alkenes
and alkynes using the reductive and oxidative quenching of [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 and [Ru(bpy)3]Cl2 is presented. Initial
investigations indicated that the oxidative quenching of photocatalysts could effectively be utilized for ATRA, and since that report,
the protocol has been expanded by broadening the scope of the reaction in terms of the photocatalysts, substrates, and solvents. In
addition, further modifications of the reaction conditions allowed for the efficient ATRA of perfluoroalkyl iodides onto alkenes and
alkynes utilizing the reductive quenching cycle of [Ru(bpy)3]Cl2 with sodium ascorbate as the sacrificial electron donor. These results
signify the complementary nature of the oxidative and reductive quenching pathways of photocatalysts and the ability to predictably
direct reaction outcome through modification of the reaction conditions.
Z
Z
X
Introduction
R1
R
X
R
With the combined efforts of several research groups,1 atom
transfer radical addition (ATRA) has been developed as a highly
useful synthetic transformation. ATRA allows for efficient al-
kene or alkyne difunctionalization, typically through the use of
radical initiators or transition metal catalysts.2 Recent efforts
have been aimed at replacing and improving these conventional
radical initiator systems3 with the eventual goal of developing
an ATRA protocol with broad generality and scalability under
mild conditions. We hypothesized that it would be possible to
utilize visible light-active photocatalysts4,5 to develop an ATRA
protocol with the following features: simple reaction setup,
mild reaction conditions, minimal side reactions, optimal cata-
lytic efficiency, and straightforward purification.
Z = initiator
Propagation
R
R1
X
R
R1
R
X
visible light
*PCn
PCn
X
R
R1
R
R1
X
R
R1
X
R
PC(n+1)
Oxidative
Quenching
R1
Recently, we realized our goal of performing ATRA between
activated halides and alkenes utilizing visible light photocataly-
sis.6 This ATRA protocol provided high yields under mild reac-
tion conditions. In terms of substrate scope, only activated
bromides and iodides were susceptible to the reaction condi-
tions and reaction times varied from 6 h to 48 h to achieve high
R
visible light
*PCn
X
PCn
R
R
R1
Reductive
Quenching
X
R
X
PC(n-1)
R
R1
R1
or
[reductant]
R
R1
or
reductant
Figure 2. Mechanistic pathways toward ATRA.
conversions. In addition, the protocol was restricted to non-
conjugated terminal olefins. Herein, we report the realization,
development, and the recent advancements of visible light-
mediated photocatalytic ATRA in terms of the photocatalysts,
substrates, and solvents (Figure 1). In particular, a remarkably
efficient perfluoroalkyliodination is presented as a viable alter-
native to classical methods to introduce perfluorinated tags
onto alkenes and alkynes. Collectively, these results demon-
Figure 1. Scope and features of visible light-mediated ATRA.
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Journal of the American Chemical Society
strate that both reductive quenching, which can be achieved in
the presence of an external electron donor, and oxidative
quenching of photocatalysts can effectively be utilized for
ATRA transformations. Furthermore, the possibility of radical
chain propagation1c possessing productive termination events is
presented as a probable parallel mechanism (Figure 2).
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Results and Discussion
of indoles, pyrroles and furans (Scheme 1A).9 Although we were
Initial observation of visible light–mediated ATRA. The
utilization
of
the
oxidative
quenching
of
able to circumvent the issues highlighted by eq 2 using a mech-
anism-based analysis, the use of such amines is not ideal, be-
cause they are expensive and used in super-stoichiometric quan-
tities. In addition, their generality with respect to catalysts, sol-
vents, and substrate scope appears to be limited.
While investigating the use of 4-MeO-C6H4-NPh2 as an elec-
tron donor, we isolated an ATRA product while performing a
6-exo-trig cyclization of a bromomalonate derivative onto a teth-
ered indole moiety as depicted in Scheme 1B. Even though the
mechanism for this transformation is still elusive, we realized
that ATRA products could be obtained by means of our photo-
catalytic approach toward general C–C coupling reactions.
Scheme 1. Utilizing 4-MeO-C6H4-NPh2 as an Electron Donor
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6 (1) for ATRA was prompted by
earlier observations of ATRA products using the reductive
quenching of [Ru(bpy)3]Cl2 (2) and [Ir(ppy)2(dtbbpy)]PF6 (3)
(Figure 3).
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Figure 3. Photocatalysts commonly used for organic synthesis.
Recently, we reported a reductive intramolecular radical cy-
clization of alkyl bromides onto unactivated -systems, exempli-
fied by the cascade radical cyclization in eq 1.7 The reductive
quenching of 2 and 3 using Et3N as a stoichiometric electron
donor was found to provide cyclized products in good to excel-
lent yields. However, only substrates containing an activated C–
Br bond, such as bromomalonate derivatives, were susceptible
to these conditions. In addition to this limitation, the protocol
was shown to be restricted to intramolecular transformations
when employing tertiary amines having α-C–H functionalities
as electron donors.
Visible light–mediated ATRA. We were pleased when we
applied our visible light photoredox catalysis conditions and
exclusively isolated the ATRA product from an intramolecular
cyclization that provided a bromo bicyclo[4.3.0]nonane deriva-
tive (eq 3). The reaction was found to be very substrate depend-
ent and preferentially gave the cyclization-reduction product
[Ru(bpy)3]Cl2 (1.0 mol %)
Et3N (2.0 equiv)
CO2Me
Br
MeO2C CO2Me
MeO2C
(1)
DMF, visible light
69%
For intermolecular reactions and unfavorable intramolecular
cyclizations, the desired C–C coupling products are kinetically
disfavored, as compared to hydrogen abstraction and enamine
coupling, the two most prominent side reactions. Amines, such
as Et3N, produce ammoniumyl radical ions upon single electron
oxidation. These radical cations are excellent hydrogen atom
donors that can give rise to dehalogenated byproducts as illus-
trated by the formation of the reduced malonate derivative in
eq 2. Furthermore, subsequent formation of iminium ions and
enamines provides other nonproductive reaction pathways, as is
evident from the acetaldehyde byproduct shown in eq 2.8
These shortcomings were successfully addressed using 4-
methoxy-N,N-diphenylaniline (4-MeO-C6H4-NPh2), an electron-
rich aromatic amine lacking α-C–H bonds, as an electron do-
nor for the efficient intermolecular C–H functionalization
with terminal alkenes and alkynes, as illustrated in eq 1. The
strong substrate dependence is emphasized by the reaction of
the closely related cyclopentene substrate that gave a 9:1 mix-
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Journal of the American Chemical Society
ture of a bromo bicyclo[3.3.0]octane derivative and the cycliza-
tion-reduction product, respectively (eq 4). Not surprisingly, all
1
attempts to perform the intermolecular ATRA with these con-
ditions resulted only in dehalogenation of starting material (eq
5).
2
3
4
5
6
7
8
9
LiBr
(mol %)
time
(h)
yielda
(%)
entry
solvent
5 (equiv)
To avoid the problems associated with the use of stoichio-
metric amine electron donors, we opted to exploit the oxidative
quenching of 1.10 In this case, the excited state of 1 would serve
as the active single electron reductant, thereby eliminating the
need for a sacrificial electron donor. With this strategy, we
managed to conduct intermolecular ATRA reactions (eq 6–8)
between various activated haloalkanes and unactivated alkenes
in high yields without detection of the reduced product. Of
1
2
DMF/H2O (1:4)
DMSO
HFIP
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.2
200
200
200
200
200
200
200
200
200
100
50
10
6
99
99
93
95
95
74
47b
28b
72
98
96
95
94
98
3
7
4
MeCN
H2O
20
7
5
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6
THF
20
24
24
12
6
7
EtOAc
DCM
8
9
MeOH
DMSO
DMSO
DMSO
DMSO
DMSO
10
11
12
13
14
6
10
7
10
7
10
8
aIsolated yield (%) after purification by chromatography on
SiO2. bFull consumption of starting material not observed.
after 24 h, although 2 provided slightly higher yields than 3. On
the contrary, the use of photocatalyst 4 resulted in incomplete
consumption of the starting material, possibly due to the low
solubility of 4 in the DMF/H2O solvent system (Table 1). For
reasons associated with accessibility and lower cost of 2 as com-
pared with 1, we chose to proceed with further studies employ-
ing photocatalyst 2.14
particular significance was the successful trifluoromethylation
of terminal alkenes, because CF3I (–1.52 V vs. SCE)11 appears
difficult to reduce with the excited state of 1 (Ir4+/Ir3+* = –0.89
V vs. SCE)12 based solely upon the comparison of redox poten-
tials (eq 8).13 The protocol is characterized by mild conditions,
high yields, and broad functional group tolerance.6 Encouraged
by the success of this atom transfer protocol, we sought to im-
prove the overall conditions and expand the method to encom-
pass a broader substrate scope.
Catalyst, solvent, and substrate screening. Our first effort to
improve the atom transfer protocol involved a more compre-
hensive screen of photocatalysts. Utilizing the conditions opti-
mized for the intermolecular ATRA between diethyl bromoma-
lonate and 5-hexen-1-ol with [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 (1),
we screened [Ru(bpy)3]Cl2 (2), [Ir(ppy)2(dtbbpy)]PF6 (3), and
Ir(ppy)3 (4) . The photocatalysts 2 and 3 both provided full con-
sumption of starting material and high yields of the product
Table 1. Catalyst Screeninga
The generality of the atom transfer protocol was then evalu-
ated with respect to the solvent (Table 2). Highly polar solvents
such as DMSO, hexafluoroisopropanol (HFIP), MeCN, and
H2O all provided the atom transfer of diethyl bromomalonate
onto 5-hexen-1-ol cleanly and in high yields (Table 2, entries 1–
5). In particular, DMSO afforded full consumption of the start-
ing material in the shortest time frame (Table 2, entry 2). Alt-
hough MeOH did provide the desired product, the crude reac-
tion mixture gave partial transesterification of the product,
which resulted in a lower isolated yield of the desired product
(Table 2, entry 9). Less polar solvents such as THF, EtOAc and
DCM typically gave complex reaction mixtures and lower yields;
longer reaction times did not increase the yields significantly
(Table 2, entry 6–8). With DMSO as the solvent, we observed
that lowering the loading of the halogenated coupling partner
from 2.0 equivalents to 1.2 equivalents and LiBr from 200 mol
% to 10 mol % only slightly increased the reaction time but did
not lower the yield (Table 2, entry 14). These new optimized
conditions offer several advantages when compared to the orig-
inal conditions: a nearly equimolar ratio of alkene and atom
transfer coupling partner, a photocatalyst that is commercially
available and more cost efficient to synthesize, reduced loading
of Lewis acid additive to sub-stoichiometric quantities, and a
solvent system capable of overcoming most solubility issues. To
evaluate the improved reaction conditions (1.0 equiv alkene,
1.2 equiv atom transfer agent, 10 mol % LiBr for α-bromo car-
bonyls, 2 mL DMSO/mmol alkene, and 1.0 mol % 2) in terms
of the substrate scope, we repeated several of our previously
published coupling reactions. We observed that yields were
comparable and, in some cases, even higher with our newly
developed reaction conditions (Table 3).
entry
catalyst
yield (%)b
1
2
3
4
5
none
0
1
2
3
4
99
99
93
35
b
a24 h reaction time. Isolated yield (%) after purification by
chromatography on SiO2.
Table 2. Solvent Screening
Table 3. ATRA Using Photocatalysisa
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Page 4 of 10
combination with the new conditions. We speculated that the
1
2
3
4
5
6
7
8
successful atom transfer of CCl4 onto norbornene was due to a
combination of the inherent strain energy of norbornene and
its increased solubility in DMSO. However, we subsequently
observed the successful coupling of CCl4 and 5-hexen-1-ol with
either 1 or 2 in DMSO (eq 9), whereas neither catalyst gave the
ATRA product in the DMF/H2O solvent system in which solu-
bility was not an issue. This indicates that DMSO is not only
superior to the DMF/H2O solvent system with regard to solu-
bility but also with regard to promoting the atom transfer radi-
cal addition process. In addition to norbornene, β-pinene, sty-
rene, and α-methyl styrene were also successful coupling part-
ners with several halogenated compounds; however, high yields
for the ATRA of CCl4 required the use of 1 rather than 2 in all
cases (Scheme 2).
Motivated by our successful enhancement of the ATRA pro-
tocol, we next sought to develop a fluorous tagging protocol of
alkenes and alkynes utilizing perfluoroalkyl iodides that would
rival known protocols in terms of efficiency (reaction time and
yield), mild reaction conditions, and functional group toler-
ance.
yield(%) yield(%)
entry RX
olefin
product
with 1b,d with 2c,d
1
2
99
92
99
94
5
5
9
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3e,f
81
75
90
88
6
7
4
Scheme 2. Expansion of Photocatalytic ATRA via Oxidative
5g
6e
99c
87
99c
95
8
9
Quenching18
b
a24 h reaction time unless otherwise noted. Reactions con-
ducted using 1.0 mol % 1, 2.0 equiv of haloalkane or haloester,
and 2.0 equiv of LiBr in H2O/DMF (4:1). Reactions conducted
using 1.0 mol % 2, 1.2 equiv of haloalkane or haloester, and 10
mol % of LiBr in DMSO. Isolated yield (%) after purification on
c
d
SiO2. eNo LiBr added. f48 h reaction time. gdr 1:1.
In an effort to further broaden the substrate scope and thus
achieve a high degree of generality of the ATRA protocol, we
revisited substrates that were not compatible with our original
conditions. Specifically, utilizing the oxidative quenching cycle
of 1, we were previously unable to effect the atom transfer onto
styrene derivatives and 1,2-disubstituted alkenes (with the ex-
ception of cyclohexene in eq 7). In addition, we failed to couple
CCl4 to any of the olefins (eq 9), even though the excited state
reduction potential of 1 (Ir4+/Ir3+* = –0.89 V vs. SCE)12 should
be sufficient to reduce CCl4 (–0.78 V vs. SCE).15 We began this
portion of our investigation using norbornene and β-pinene,
because these strained alkenes are known to be more reactive
than cyclohexene.16
Introduction to fluorous tagging. The fluorous biphasic
concept19 was introduced to the field of organic synthesis in the
mid 1990’s, and since then, the special properties of perfluori-
nated carbons have been innovatively utilized for the synthesis
of small molecules.20 The introduction of perfluorinated tags in
conjunction with solid phase extraction (F-SPE) by Curran and
co-workers21 made an especially crucial impact on both indus-
trial and academic research in the context of conventional,
parallel and combinatorial syntheses.22,23 By temporary attach-
ment or permanent affixation of a perfluorinated alkyl chain to
reagents or reactants, product isolation in reactions that typical-
ly have been tedious and laborious are now promptly performed
by either multiphasic solvent systems or by SPE techniques,
utilizing either heavy (>60% fluorine by weight) or light (<40%
fluorine by weight) perfluorous molecules, respectively. Even
though several perfluorinated compounds of various sizes are
commercially available, the development of novel methods for
efficient and selective introduction of fluorinated motifs is a
growing area of interest because of the expansion of its applica-
tions within the research fields of medicinal, synthetic, indus-
trial, and agricultural chemistry.24
Utilizing our originally optimized conditions, the ATRA of
CCl3Br to norbornene was sluggish, partly attributable to the
low solubility of norbornene in DMF/H2O. However, the newly
optimized conditions utilizing DMSO and 2 provided a homo-
geneous reaction mixture and the atom transfer addition prod-
uct in high yield (Scheme 2). Dibromodifluoromethane
(CF2Br2)17 and 4-toluenesulfonyl chloride (TsCl) with nor-
bornene also provided the corresponding ATRA products in
high yields, but the ATRA product of CCl4 and norbornene
could only be achieved in high yield when 1 was utilized in
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Journal of the American Chemical Society
Perfluorinated motifs can be incorporated both under stoi-
solvents and was diminished in less polar solvents. No product
formation was observed in the absence of catalyst or a visible
light irradiation source.32
chiometric25 and catalytic26 conditions. Addition reactions of
perfluoroalkyl iodides to alkenes and alkynes represent one of
the most common means to synthesize fluorous compounds.
This type of transformation can be accomplished photochemi-
cally (UV), thermally (>200 °C), electrochemically, or through a
redox active system.27 During our investigation of visible light-
1
2
3
4
5
6
7
8
After the successful intermolecular ATRA of C8F17I onto 5-
hexen-1-ol, the reaction scope toward structurally diverse per-
fluoroalkyl iodides was examined. As expected, high to excellent
yields were obtained for various perfluoroalkyl iodides (Table 5)
with a small decrease in yield for shorter C6F13I (Table 5, entry
2) and branched (CF3)2CFI (Table 5, entry 5). A plausible ex-
planation for this drop in yield for C6F13I is that shorter per-
fluoroalkyl iodides have a more negative reduction potential. In
the case of (CF3)2CFI the drop in yield probably stems from
steric effects rather than redox properties.33
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The scope and functional group compatibility of the opti-
mized conditions of the intermolecular ATRA between C8F17I
and various terminal alkenes and alkynes were also evaluated
Table 4. Optimization of Reaction Conditions
Figure 4. Photoredox-mediated atom transfer radical additions
have been extended to perfluoroalkyl iodides onto alkenes and
alkynes utilizing the reductive quenching cycle of [Ru(bpy)3]Cl2.
mediated ATRA of activated halides across double bonds utiliz-
ing the oxidative quenching catalytic cycle of 1, we managed to
access trifluoromethylated alkanes in high yields (Table 3, entry
3 and eq 8). However, a large excess of CF3I, high boiling sol-
vents (DMF or DMSO), and long irradiation times (48 h) were
required for high conversions. These disadvantages encouraged
us to further develop and expand our ATRA protocol within
the field of fluorous chemistry (Figure 4).
time
(h)
yieldg
(%)
entry cat.
solvent
reductant
1
2a
3
1
2
4
2
2
2
2
2
2
2
2
DMF
DMSO
-----
-----
24
5
N.R.
95
43
10
73
58
25
99
91
99
67
DMF
-----
H.E.f
iPr2NEt
216
5
4
MeCN
A general iodoperfluoroalkylation of alkenes and alkynes.
Initially, we sought to apply the optimized conditions for the
ATRA (Table 3, entry 3), mediated by the oxidative quenching
of 1 or 2, to the ATRA of a variety of perfluoroalkyl iodides. It
is well known that longer chain perfluoroalkyl iodides are more
easily reduced (less negative reduction potentials) than CF3I.28
Therefore, we reasoned that the oxidative quenching of 1 and 2
would promote the ATRA of perfluoroalkyl iodides such as
C8F17I with high efficiency. Surprisingly, no conversion was
observed after 24 h when C8F17I (–1.32 V vs. SCE) and 5-hexen-
1-ol were reacted with photocatalyst 1 (Table 4, entry 1). We
then turned to our newly improved conditions utilizing 2 in
DMSO, which generated the desired product in 95% yield
within 5 h (Table 4, entry 2). However, we continued screening
conditions with the expectation that we could lower the reac-
tion time while maintaining high yields by using a catalyst with
a stronger reducing capacity. When employing photocatalyst 3,
which has a much stronger excited state reduction potential (–
1.73 V vs. SCE) than 1 or 2,29 the desired product was isolated
in only 43% yield after 9 days (Table 4, entry 3). These unsatis-
factory results led us to revisit the reductive quenching cycle of
2. Initially, we were uncertain about relying on the reductive
quenching cycle due to the issues of prominent side reactions
(vide supra). Nevertheless, the advantages of using 2 as the pho-
tocatalyst include its low cost and the relatively strong reductive
power of [Ru(bpy)3]+ (–1.33 V vs. SCE).30
Prompted by this reassessment, we screened various stoichi-
ometric reductants for 2 (Table 4, entries 4–7), and the desired
product was isolated in yields ranging from 10% to 73% after 5
h of irradiation. We observed low solubility of sodium ascor-
bate31 in acetonitrile and consequently found that the addition
of either a phase transfer catalyst, such as hexadecyltrime-
thylammonium bromide, or the use of MeOH as co-solvent led
to significant improvements in both yield and reaction time
(Table 4, entries 8–9). Thorough optimization of the reaction
conditions provided a 99% yield in just 0.5 h (Table 4, entry
10). The efficiency of the reaction was preserved in other polar
5
MeCN
5
6
MeCN
Bu3N
5
7
8b
MeCN
Na-ascorbate
Na-ascorbate
Na-ascorbate
Na-ascorbate
Na-ascorbate
5
MeCN
1.5
0.5
0.5
0.5
b
9
MeCN/MeOHe
MeCN/MeOHe
MeCN/MeOHe
10c
11d
aReaction conducted using C8F17I (1.2 equiv). Hexadecyltrime-
thylammonium bromide used as an additive. 1.3 equiv of per-
c
fluoroalkyl iodide and 0.35 equiv of sodium ascorbate were used.
d1.3 equiv of perfluoroalkyl iodide and 0.05 equiv of sodium
e
f
ascorbate were used. 4:3 mixture. H.E. = Hantzsch ester (Diethyl
1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate). gIsolated yield
(%) after purification by chromatography on SiO2.
Table 5. ATRA of Various Perfluoroalkyl Iodides
entry
substrate
time (h)
yield (%)c
1a
2b
3
CF3I
C6F13I
48
0.5
0.5
0.5
0.5
90
81
99
97
81
C8F17I
4
C10F21I
(CF3)2CFI
5
aSee eq 8. b2.0 equiv of both perfluoroalkyl iodide and reductant
c
were used. Isolated yield (%) after purification by chromatography
on SiO2.
(Table 6). In general, yields were high to excellent for a wide
variety of substrates with the exception of styrene derivatives.
Although the addition of perfluoroalkyl radicals onto styrene
derivatives has been performed using radical initiators,34 elec-
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tron neutral, poor and rich styrenes all produced complex reac- suitable partners in this ATRA protocol. However, the opti-
1
2
3
4
5
6
7
8
tion mixtures from which the corresponding product could not
be isolated (Table 6, entry 11). Side reactions, such as polymeri-
zation, might arise from reduction or oxidation of either prod-
uct or alkene starting material by the catalyst. However, non-
conjugated alkenes substituted with electron-deficient aromat-
ics, such as 2-bromo-4-(but-3-en-1-yl)pyridine (Table 6, entry 10),
as well as alkenes substituted with non-conjugated electron-rich
aromatics (Table 6, entry 8) afforded the product in high yields.
Of significant importance is that both aromatic and alkyl bro-
mides and iodides are compatible with these mild reaction con-
ditions (Table 6, entries 2, 6, 8 and 10). Alkenes containing
allylic N- and O-carbamate functionalities, frequently utilized as
fluorous-tagged protecting groups for amines and alcohols, gave
high to excellent yields, as did acetals (Table 6, entries 4, 5 and
9). Multi-gram scale reactions were performed without signifi-
cant decrease in yields within the optimized reaction time of
Table 6. Substrate Scope
mized conditions that provided exclusive ATRA products for
alkenes gave significant quantities of reduced byproducts for all
alkynes investigated. This problem was successfully addressed by
changing the solvent system from MeCN/MeOH to t-
BuOH/H2O providing the corresponding perfluorovinyl io-
dides in high yields (Table 6, entries 12 and 13). Assuming that
propagation is a non-active mechanistic component (vide infra),
the turnover number (TON) of the catalyst is ~104 and the
turnover frequency (TOF) is > 5.3 s-1.
9
The high efficiency and broad functional group compatibility
of this system prompted an investigation of its potential for the
strategic introduction of perfluorinated tags in the synthesis of
structurally complex molecules. Curran and co-workers intro-
duced the concept of fluorous scavenging to facilitate small
molecule synthesis in terms of a general strategy for product
isolation.36 Similarly, post-transformational introduction of
perfluorinated tags to alkene-functionalized protecting groups
or reagents via the present protocol would circumvent possible
solubility issues and/or other impeding properties imposed by
perfluorinated tags. In addition, this method also provides the
possibility to tune the fluorous nature of substrates and cata-
lysts. The validity of this hypothesis was evaluated by fluorous
post-transformational quenching (F-PTQ) of alkene-
functionalized phosphine reagents in both Wittig (Scheme 3A)
and Mitsunobu reactions (Scheme 3B). Both transformations
are known to produce byproducts that are problematic during
product isolation. Several strategies have been employed to
address this issue,37 including fluorous techniques,38 which
suggested that they would be suitable test systems for the evalua-
tion of the general applicability of this protocol. For the Wittig
reaction, phosphonium salt 14 was treated with n-BuLi, fol-
lowed by p-chlorobenzaldehyde, providing a crude reaction mix-
ture consisting of stilbene derivative 15 and a phosphine oxide
functionalized with a terminal alkene. Subjecting the crude
reaction mixture to F-PTQ with a prolonged irradiation time,
followed by F-SPE,Error! Bookmark not defined. allowed for
the isolation of the pure product 16 in 74% yield (94:6 dr). As a
consequence of excited state quenching (energy transfer) of the
catalyst by the stilbene derivative, a longer reaction time was
needed for full consumption of the phosphine oxide. In addi-
tion, because the (E)-stilbene has a smaller HOMO-LUMO gap
than (Z)-stilbene, the excited state quenching also explains the
high diastereoselectivity toward the (Z)-diastereoisomer.39 For
the Mitsunobu reaction, N-tosylaniline and EtOH were treated
with phosphine 17 and fluorous tagged DIAD (F-DIAD)
providing a crude reaction
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
substrate
t (h)
0.5
yield (%)g
99 (96%)a
93
1
2
0.5
3
4
5
0.5
0.5
0.5
94
96
79
6
7
0.5
0.5
94
90
8
4
99
9
0.5
2
91b
10
88 (85%)c
11
0.5 - 24
0d
Scheme 3. Post-Transformation Fluorous Quenching
12
13
0.5
0.5
96e
94f
aYield in parentheses is for a preparative reaction (4.0 g, 40
b
mmol) using 0.01 mol % catalyst. 1:1 dr. cYield in parentheses is
for a preparative reaction (1.6 g, 7.5 mmol) using 0.1 mol % cata-
d
lyst. Partial consumption of starting material. For all substrates, a
complex reaction mixture was obtained or the targeted product was
e
f
g
unstable and thus not successfully isolated. 1.8:1 dr. 2:1 dr. Iso-
lated yield (%) after purification by chromatography on SiO2.
0.5 h (Table 6, entries 1 and 10). Furthermore, on large scale
(40 mmol) only 0.01 mol % of 2 was needed to obtain a yield of
96% for ATRA with C8F17I and 5-hexen-1-ol.35 Alkynes are also
mixture consisting of product 18, excess phosphine 17, phos-
phine oxide from 17, excess F-DIAD, and fluorous tagged hy-
drazine. The crude mixture was once again subjected to F-PTQ
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Journal of the American Chemical Society
to the reaction conditions or refluxed in toluene, the formation
to tag the excess phosphine and phosphine oxide. After 2.5
1
2
3
4
5
6
7
8
hthe reaction was subjected to F-SPE to provide the pure prod-
uct in 92% yield.
of 20 is not observed. In addition, the treatment of 19 with
base generated cyclopropane 21 as the only product. These
observations strongly indicate that 20 is not generated from 19
but rather from the nucleophilic trapping of a carbocation in-
termediate by the tethered alcohol. Further support for a radi-
cal-polar crossover mechanism was obtained through an inter-
molecular trapping experiment in which carbon tetrachloride
(2.0 equiv) and 5-hexen-1-ol were subjected to the newly devel-
oped conditions, using [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 (1.0 mol
%) and DMSO in the presence of excess KBr (2.5 equiv)
(Scheme 5B). After 24 hours of irradiation a mixture of the
corresponding chloride and bromide ATRA products, 22 and
23, respectively, were isolated in 35% yield in a 2.5:1 molar
ratio favoring the chloride product 22. Neither the resubjection
of 22 to the reaction conditions nor the presence of 18-crown-6
to increase the nucleophilicity of bromide produced detectable
amounts of 23, which further suggest that the formation of 23
is the result of nucleophilic trapping rather than a displacement
reaction of the secondary chloride of 22 with bromide.
Discussion of plausible reaction mechanisms. Both the re-
ductive and oxidative quenching cycles are initiated by activa-
tion of the photocatalyst by visible light absorption to produce
3
the MLCT state of the catalyst (Scheme 4). In the presence of
an electron donor, the excited state is reductively quenched
providing a reduced catalyst (*PCn/PCn-1, PC = photocatalyst).
For the fluorous tagging protocol, *[Ru(bpy)3]2+ is reduced to
[Ru(bpy)3]+ using sodium ascorbate as the electron donor.
[Ru(bpy)3]+ has a sufficiently strong reduction potential (–1.33
V vs. SCE) to effectively convert perfluoroalkyl iodides (–1.0 to
–1.5 V vs. SCE) to electrophilic free radicals. The radical then
undergoes addition to the alkene or alkyne. The ATRA product
can subsequently be formed via two different routes: either by
propagation or by oxidation to the cation followed by nucleo-
philic trapping in accordance with the oxidative quenching
pathway as outlined in Scheme 4. The oxidation potential of
secondary radicals (0.47 V vs. SCE)40 renders them prone to
oxidation by the photocatalyst, consequently initiating another
catalytic cycle. Nucleophilic trapping with iodide, possibly pre-
associated as a counterion to the catalyst, provides the ATRA
product. For ATRA using classical radical initiators, propaga-
tion has been shown to be an operative mechanism and can
also be a viable mechanistic component in this catalytic system.
For either route, sodium ascorbate acts only as an initiator to
provide the initial [Ru(bpy)3]+ species. This is corroborated by
the fact that only small amounts of sodium ascorbate (0.05 mol
%) are needed for nearly complete consumption of the starting
material (Table 4, entry 11).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Evidence for a Radical-Polar Crossover Mechanism
Scheme 4. Proposed Mechanism for Photocatalytic ATRA
In the redox neutral oxidative quenching pathway, the pho-
tocatalyst reduces the halogenated substrate directly from its
100
90
80
70
60
50
40
30
20
10
0
excited state to produce an oxidized photocatalyst (*PCn/PCn+1
)
and an electrophilic radical that undergoes addition to an al-
kene. The addition produces a radical that can be oxidized to a
carbocation by the catalyst to complete the catalytic cycle and
subsequently generate the product by nucleophilic trapping of a
halide, or the radical can participate in a propagation chain to
also produce the ATRA product.
Our previous report,6 as well as new experimental evidence,
provides support for the radical-polar crossover41 mechanism
proposed for the oxidative quenching of photocatalysts (Scheme
4). When the ATRA of diethyl bromomalonate (1.2 equiv) was
performed with 4-penten-1-ol, LiBr (1.2 equiv), and
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6 (1.0 mol %) in DMF/H2O, the
tetrahydrofuran byproduct 20 was isolated in 10% yield
(Scheme 5A). When the atom transfer product 19 is resubjected
0
2
4
6
8
10
12
14
In addition to the trapping investigations, we performed an
experiment designed to verify the necessity of light to maintain
the ATRA reaction. A mixture of diethyl bromomalonate (2.0
equiv),
5-hexen-1-ol,
LiBr
(1.1
equiv),
and
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6 (0.05 mol %) in DMF/H2O was
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Page 8 of 10
ratio favoring 26. Similarly, adding ethyl bromoacetate to a
stirred for 14 h, alternating between 2 h periods of visible light
1
2
3
4
5
6
7
8
irradiation and 1 h periods of complete lack of visible light
irradiation until consumption of 5-hexen-1-ol was judged to be
complete (Scheme 5C). It was observed that the reaction pro-
gressed steadily with visible light irradiation, but consumption
of the alkene abruptly stalled when the light source was re-
moved. The results of this experiment neither definitively con-
firm a radical-polar crossover mechanism nor definitively negate
a radical chain propagation mechanism, although it is clear that
visible light is a necessary component of the reaction. However,
if propagation is an active mechanistic component it is evident
that the propagating chain reactions are short-lived. Therefore,
it is reasonable to assume that when using only 0.05 mol % of
catalyst, regeneration of the catalyst via oxidation of an alkyl
radical to an alkyl cation to initiate the short chain propagation
is necessary for full consumption of the alkene. This oxidation
constitutes closure of the catalytic cycle and serves as a produc-
tive formal termination step.
Although the intra- and intermolecular trapping experiments
in combination with the indirect evidence obtained from the
“light/dark” experiment provides strong evidence for a radical-
polar crossover mechanism (vide supra), propagation cannot be
ruled out as a competing parallel mechanism. To assess if prop-
agation can be an active mechanistic pathway, we identified an
effective probe for propagation, ethyl bromoacetate (Scheme
6A). Ethyl bromoacetate does not undergo ATRA via oxidative
quenching with our reaction conditions when 1 is utilized as
the catalyst. Therefore, the addition of ethyl bromoacetate to a
reaction mixture of ethyl bromofluoroacetate, 1, 5-hexen-1-ol,
LiBr, and DMF/H2O should only lead to the formation of 25 if
Scheme 6. Evidence for Propagation Mechanism
reaction mixture of diethyl bromomalonate, 1, 5-hexen-1-ol,
LiBr, and DMF/H2O gave a product mixture of 24 and 26 in
90% yield with a 1:1 molar ratio. These two experiments un-
ambiguously demonstrate that propagation can occur when
oxidative quenching of photocatalysts is utilized, although the
differing product ratios illustrate the substrate dependence on
the degree of propagation. An illustrative example in which
propagation is most likely completely operative is the successful
ATRA of perfluoroalkyl iodides onto alkynes. In this case,
propagation is a much more likely reaction pathway then the
thermodynamically unfavored oxidation of a vinyl radical to a
vinyl cation (Scheme 6B).
A plausible mechanistic rationale for the oxidative quenching
of 1 and 2 involves visible light-mediated initiation of a chain
propagation that provides the ATRA product. Termination of
the propagation via oxidation of the radical to the carbocation
by the catalyst, thus completing a photocatalytic cycle, provides
the ATRA product by nucleophilic trapping, and also regener-
ates the ground state catalyst (PCn). Therefore, the use of a pho-
tocatalyst as an initiator for ATRA contrasts with traditional
radical initiators in that the termination process is a productive
event. To which extent radical propagation or radical-polar
crossover contribute to the overall yield is most likely highly
dependent on the nature of the substrates and the conditions
used (i.e. which catalyst and which solvents are employed) and
if the reductive or oxidative quenching pathway is utilized.
Although both quenching pathways lead to the same prod-
uct, there are essential differences worth noting. The reduction
potentials for *[Ir{dF(CF3)ppy}2(dtbbpy)]+ and *[Ru(bpy)3]2+ are –
0.89 V and –0.86 V vs. SCE, respectively, for oxidative
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
quenching,
whereas
the
reduction
potential
of
A)
[Ir{dF(CF3)ppy}2(dtbbpy)] is –1.37 V vs. SCE and –1.33 V vs.
SCE for [Ru(bpy)3]+ for reductive quenching. Due to the nature
of these metal-centered complexes, the reduction potential for a
photocatalyst when applying the oxidative quenching pathway
is less negative than when utilizing the reductive quenching
pathway. This is illustrated by the longer reaction times and the
requirement of using Lewis acid additives (i.e. LiBr) when α-
bromo carbonyls are used for ATRA via oxidative quenching.
In this case, the Lewis acid coordination makes the carbon-
halogen bond more prone to reduction and, therefore, to free
radical formation.6 In contrast, the reductive quenching cycle
utilizes a reductive quencher to access a stronger reductant (PCn-
1) to achieve the reduction of the carbon-halogen bond without
the need for a Lewis acid. This ability to effect the same trans-
formation by carefully optimizing the reaction conditions for
either oxidative or reductive quenching of a photocatalyst illus-
trates the complementary nature of the two quenching path-
ways.
OH
EtO2C
CO2Et
(0.5 equiv)
EtO2C
+
F
EtO2C
Br
(2.0 equiv)
(0.5 equiv)
Br
Br
+
+
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6 (1)
(1.0 mol %)
EtO2C
Br
EtO2C
+
Br
(10 equiv)
(10 equiv)
LiBr (2.0 equiv)
+
DMF/H2O (1:4)
visible light
1 (1.0 mol %)
LiBr (2.0 equiv)
DMF/H2O (1:4)
visible light
1 (1.0 mol %)
LiBr (2.0 equiv)
DMF/H2O (1:4)
visible light
EtO2C
Br
OH
OH
F
Br
OH
OH
no reaction
EtO2C
EtO2C
24 (45%)
25 (22%)
Br
Br
EtO2C
EtO2C
26 (62%)
26 (45%)
B)
propagation
favorable pathway
[Ru(bpy)3]Cl2 (1.0 mol %)
C8F17I (1.3 equiv)
Na-ascorbate
Conclusion
I
(0.35 equiv)
F17C8
F17C8
During our pursuit to develop efficient reductive cyclization
and intermolecular coupling reactions by means of visible light
photocatalysis, we observed the formation of ATRA products.
As a consequence of these observations we realized that redox
neutral coupling products might be obtained by our photocata-
lytic approach towards general CC coupling reactions. The
reductive quenching conditions optimized for reductive cou-
pling and cyclization reactions with tertiary amines as stoichio-
metric electron donors did not produce efficient and general
ATRA transformations. We consequently turned to the oxida-
tive quenching pathway and successfully employed
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6 in the photocatalytic ATRA be-
OH
OH
t-BuOH/H2O (6:1)
visible light, 24 h
*Ru(II)
I
Ru(I)
F17C8
OH
OH
unfavorable pathway
a radical-polar crossover mechanism is the only operative mech-
anism. However, if a propagation mechanism is operative then
it may be possible to observe the ATRA product of ethyl bro-
moacetate. In fact, the ATRA product of ethyl bromoacetate
(26) was indeed obtained as a mixture with the ATRA product
of ethyl bromofluoroacetate (25) in 84% yield as a 1:2.8 molar
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Journal of the American Chemical Society
tween various activated halides and alkenes. Even though this
protocol efficiently mediated the ATRA between terminal al-
1
2
3
4
5
6
7
8
Weidner, G. K.; Giroult, A.; Panchaud, P.; Renaud, P. J. Am. Chem.
Soc. 2010, 132, 17511.
(2) Muñoz-Molina, J. M.; Belderrain, T. M.; Pérez, P. J. Eur. J. Inorg.
kenes and activated alkyl bromides and iodides, the reaction
conditions were not amenable to activated alkyl chlorides, 1,2-
disubstituted alkenes, or styrene derivatives. However, these
limitations were resolved by utilizing [Ru(bpy)3]Cl2 or
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6 in DMSO instead of a DMF/H2O
mixture.
Chem. 2011, 21, 3155.
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lyst, reactions originating from sacrificial electron donors are
avoided. However, this somewhat restricts the reductive ability
of the catalyst and limits the substrate scope. These shortcom-
ings were addressed successfully during the development of a
highly efficient and mild protocol to effect fluorous tagging of
both alkenes and alkynes. By utilizing sodium ascorbate as an
inexpensive substoichiometric electron donor, we managed to
bypass shortcomings associated with the use of tertiary amines
as electron donors. The ATRA reaction has a broad functional
group tolerance and is competent with structurally diverse per-
fluorinated alkyl iodides. Yields are high to excellent and reac-
tion times are typically 0.5 h. Furthermore, the capability of
the protocol in post-transformational quenching was illustrated
by fluorous tagging of an alkene-functionalized tri-
phenylphosphine derivative in both Wittig and Mitsunobu
reactions.
The development of ATRA via the oxidative and reductive
quenching of photocatalysts has been firmly established as a
reliable and versatile methodology. In particular, the ability to
predictably direct the reaction outcome by careful selection and
modification of the catalysts, additives, and solvents has been
presented. Further investigations of photocatalytic ATRA and
the synthetic applications of this methodology will be reported
in due course.
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ASSOCIATED CONTENT
Supporting Information. Detailed experimental procedures, spec-
troscopic data of all new compounds and a comprehensive descrip-
tion of reaction setup. This material is available free of charge via
the Internet at http://pubs.acs.org.
(6) Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.; Stephenson,
C. R. J. J. Am. Chem. Soc. 2011, 133, 4160.
(7) Tucker, J. W.; Nguyen, J. D.; Narayanam, J. M. R.; Krabbe, S.
W.; Stephenson, C. R. J. Chem. Commun. 2010, 46, 4985.
(8) Tucker, J. W.; Narayanam, J. M. R.; Krabbe, S. W.; Stephenson,
C. R. J. Org. Lett. 2010, 12, 368.
AUTHOR INFORMATION
(9) Furst, L.; Matsuura, B. S.; Narayanam, J. M. R.; Tucker, J. W.;
Stephenson, C. R. J. Org. Lett. 2010, 12, 3104.
Corresponding Author
*crjsteph@bu.edu
(10) Lowry, M. S.; Goldsmith, J. I.; Slinker, J. D.; Rohl, R.; Pascal,
R. A., Jr.; Malliaras, G. G.; Bernhard, S. Chem. Mater. 2005, 17, 5712.
(11) Andrieux, C. P.; Gelis, L.; Medebielle, M.; Pinson, J.; Saveant,
J. M. J. Am. Chem. Soc. 1990, 112, 3509.
(12) Incorrectly estimated to be -1.21 V vs. SCE in ref. 10.
(13) For the trifluoromethylation of arenes initiated by the reduc-
tion of CF3SO2Cl, see: Nagib, D. A.; MacMillan, D. W. C. Nature
2011, 480, 224.
(14) [Ru(bpy)3]Cl2 is synthesized in one step from RuCl3 (5.0 g for
$140.00 from Sigma Aldrich), whereas [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 is
synthesized in three steps from IrCl3 (5.0 g for $472.50 from Sigma
Aldrich). Also, at the time of submission, the cost of 1.0 g of
[Ru(bpy)3]Cl2 (Sigma Aldrich) was $74.10.
ACKNOWLEDGMENT
Financial support for this research from the NSF (CHE-1056568),
the Alfred P. Sloan Foundation, Amgen, and Boehringer
Ingelheim is gratefully acknowledged. C-J.W. thanks The Swedish
Research Council and The Royal Physiographic Society in Lund
for postdotoral fellowships. J.D.N. thanks AstraZeneca for a
graduate fellowship. NMR (CHE-0619339) and MS (CHE-
0443618) facilities at BU are supported by the NSF. We thank
Victor Chen, Gregory Karahalis, Marlena Konieczynska, and
Joseph Tucker for experimental assistance.
(15) Mitani, M; Kiriyama, T; Kuratate, T. J. Org. Chem. 1994, 59,
1279.
(16) Dunbar, R. C.; Hays, J. D.; Honovich, J. P.; Lev, N. B. J. Am.
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