Engaging unactivated alkyl, alkenyl and aryl iodides in visible-light-mediated free radical reactions

Article abstract of DOI:10.1038/nchem.1452

Radical reactions are a powerful class of chemical transformations. However, the formation of radical species to initiate these reactions has often required the use of stoichiometric amounts of toxic reagents, such as tributyltin hydride. Recently, the use of visible-light-mediated photoredox catalysis to generate radical species has become popular, but the scope of these radical precursors has been limited. Here, we describe the identification of reaction conditions under which photocatalysts such as fac-Ir(ppy) 3 can be utilized to form radicals from unactivated alkyl, alkenyl and aryl iodides. The generated radicals undergo reduction via hydrogen atom abstraction or reductive cyclization. The reaction protocol utilizes only inexpensive reagents, occurs under mild reaction conditions, and shows exceptional functional group tolerance. Reaction efficiency is maintained upon scale-up and decreased catalyst loading, and the reaction time can be significantly shortened when the reaction is performed in a flow reactor.

Full text of DOI:10.1038/nchem.1452

ARTICLES
PUBLISHED ONLINE: 24 SEPTEMBER 2012 | DOI: 10.1038/NCHEM.1452
Engaging unactivated alkyl, alkenyl and aryl
iodides in visible-light-mediated free radical
reactions
John D. Nguyen, Erica M. D’Amato, Jagan M. R. Narayanam and Corey R. J. Stephenson
*
Radical reactions are a powerful class of chemical transformations. However, the formation of radical species to initiate
these reactions has often required the use of stoichiometric amounts of toxic reagents, such as tributyltin hydride.
Recently, the use of visible-light-mediated photoredox catalysis to generate radical species has become popular, but the
scope of these radical precursors has been limited. Here, we describe the identification of reaction conditions under which
photocatalysts such as fac-Ir(ppy)3 can be utilized to form radicals from unactivated alkyl, alkenyl and aryl iodides. The
generated radicals undergo reduction via hydrogen atom abstraction or reductive cyclization. The reaction protocol utilizes
only inexpensive reagents, occurs under mild reaction conditions, and shows exceptional functional group tolerance.
Reaction efficiency is maintained upon scale-up and decreased catalyst loading, and the reaction time can be significantly
shortened when the reaction is performed in a flow reactor.
onventional methods for reducing alkyl, alkenyl and aryl combination with Hantzsch ester or formic acid to perform both
iodide bonds1 consist of metal–halogen exchange, a hydride reductive deiodination and intramolecular cyclization of alkyl,
C
source or radical reductive dehalogenation. Reductions utiliz- alkenyl and aryl iodides.
ing metal–halogen exchange2,3 or a hydride source4 commonly
During the last decade, several groups have demonstrated the
result in undesired side reactions, and are not functional group tol- versatility of metal-based and organic photocatalysts20 to carry out
erant. This has led to the development of alternative methods that a variety of transformations21, with beneficial applications in total
can be applied to the reductive dehalogenation of aryl halides and synthesis22. A large number of these reactions involve the generation
a-halo carbonyls5. Radical reductive dehalogenation is by far the of radical intermediates from activated carbon–halogen bonds,
most commonly utilized method for the reduction of carbon– including bromomalonates23–25, polyhalomethanes26–28, electron-
halogen bonds because the reaction conditions are typically mild deficient benzyl bromides29, a-halo carbonyls30,31 and glycosyl
and pH-neutral; reactions times are short; and product yields are bromides32. A major advantage of metal-based photocatalysts,
relatively high1. These characteristics have allowed radical chemistry such as [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 (1)33, Ru(bpy)3Cl2 (2)34,
to be used effectively for challenging bond constructions, such as Ir(dtbbpy)(ppy)2PF6 (3) and fac-Ir(ppy)3 (4)35,36 is the ease of
those performed in the syntheses of hirsutene6, amauromine7 and tuning the complex to achieve desired redox potentials through
(þ)-11,11′-dideoxyverticillin A (ref. 8). However, the radical modification of the ligands or replacement of the metal centre
initiator or hydrogen atom donor is typically toxic (for example, (Fig. 1a)37. These photocatalysts are capable of radical reductive
organotin)9, potentially explosive (azobisisobutyronitrile (AIBN) cleavage of carbon–halogen bonds by direct reduction from the
and peroxides)10, unstable to air (samarium(II) iodide)11 or pyro- excited state of the catalyst (oxidative quenching) or via two
phoric (trialkylboranes)12,13. In an attempt to avoid the toxicity single electron transfer (SET) processes, where the excited state is
associated with tributyltin hydride, other hydrogen atom donors reduced by a sacrificial electron donor followed by reduction of
have been used, such as 1,4-cyclohexadiene, triethylsilane, tris(tri- the carbon–halogen bond (reductive quenching).
methylsilyl)silane, triphenylgermane, thiols and diphenylphos-
phine, but these are less efficient, unstable and/or expensive.
Our work in the field of visible-light-mediated photoredox
catalysis has demonstrated the advantages in modifying metal-
Recent efforts have been made to improve the process of radical based photocatalysts to achieve transformations initiated by SETs.
reductive dehalogenation through replacement of the radical initiator In previous studies, we observed the intramolecular cyclization of
and the development of new hydrogen atom donors. The ground- bromomalonate-tethered p-systems via the reductive quenching of
state neutral electron donors used by Murphy14,15 and the alkyl- 2 (ref. 38). However, a-bromoester analogues did not undergo cycli-
and stannyl-cobaloxime catalysts developed by Careirra16 have zation using 2, although they cyclized efficiently when the catalyst
successfully generated alkyl radicals from alkyl iodides. In addition, was replaced with 3. In this case, modification of the ligands
several new hydrogen atom donors have been introduced, such as and replacement of the metal centre result in a more negative
N-heterocyclic carbene boranes17 and water in the presence of reduction potential for 3 (21.51 V versus saturated calomel elec-
Et3B18 or Ti(III) salts19. Ultimately, the goal is to develop a mild trode (SCE))35 than 2 (21.31 V versus SCE)34, which enables the
and efficient radical reductive deiodination protocol with broad radical cyclization of a-bromoesters onto p-systems. Another
functional group tolerance that utilizes an easy-to-handle catalyst example of effective ligand substitution is seen when the 2-phenyl-
and an inexpensive and readily accessible hydrogen atom donor. pyridyl (ppy) ligands of 3 are replaced with 2-(2,4-difluorophenyl)-
Herein, we report the use of the photocatalyst fac-tris[2-phenylpyr- 5-trifluoromethylpyridyl (dF(CF3)ppy) ligands to generate 1, a
idinato-C2,N]iridium(III) ( fac-Ir(ppy)3) and tributylamine in catalyst that has a more positive reduction potential (Ir4þ ꢀ Ir3þ
)
Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, USA. e-mail: crjsteph@bu.edu
*
854
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1452
ARTICLES
a
–
b
F3C
PF6
2Cl–
Cl3C Cl
RO2C
CCl3 Br
F
(1)
tBu
Ir(IV)/Ir(III) –0.89 V
*
CO2R
N
N
Ir
N
N
N
N
N
Br
F
F
Ru
N
F17C8
I
R
N
N
N
tBu
(2)
Br
H
Ru(II)/Ru(I) –1.31 V
F
N
F3C
R
Ru(bpy)3Cl2
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6
(2)
(1)
–
Br
R
RO2C
R
(3)
PF6
tBu
Ir(III)/Ir(II) –1.51 V
R
Br
Br
N
Ir
N
N
Ir
I
Br
N
N
N
(4)
I
Ir(IV)/Ir(III)* –1.73 V
N
tBu
EWG
Ir(ppy)2(dtbbpy)PF6
fac-Ir(ppy)3
(4)
This work
(3)
Figure 1 | Visible-light-active photocatalysts and representative examples of compounds capable of undergoing radical reductive cleavage. a, Visible-light-
active photocatalysts commonly used for photoredox catalysis. b, Through modification of the metal centre and ligands, transition-metal-based photocatalysts
may be tuned appropriately to obtain the desired redox potentials, allowing access to radical reductive cleavage of a variety of carbon–halogen bonds.
Although only the most activated carbon–halogen bonds can be reduced by the weakest reductant (1), with an appropriately strongly reducing catalyst, such
as 4, electron-deficient benzyl bromides and even unactivated alkyl, alkenyl and aryl iodides can undergo radical reductive cleavage.
Table1 | Reduction of alkyl iodides and aryl iodides.
Procedure A
Procedure B
fac-Ir(ppy)3 (1.0 mol%)
Bu3N (5.0 equiv.)
fac-Ir(ppy)3 (1.0 mol%)
Bu3N (2.0 equiv.)
Hantzsch ester* (2.0 equiv.)
HCO2H (5.0 equiv.)
Ar
I
Ar
H
R
I
R
H
MeCN, visible light
MeCN, visible light
(7a-i)
(8a-i)
(5a-i)
(6a-i)
H
BnO
H
TBDPSO
NHTs
NHBoc
NHAc
6a (92%, 20 h)
6b (84%, 24 h)
O
O
H
N
H
H
H
H
8c (95%, 44 h)
O
O
HO
8a (94%, 20 h)
8b (97%, 28 h)
6c (87%, 20 h)
6d (85%, 16 h)
O
CO2Me
NH2
H
O
H
H
O
Ph
4
O
H
Br
H
H
CO2Me
6e (82%, 18 h)
6f (90%, 12 h)
H
H
O
8d (92%, 6 h)
8e (93%, 8 h)
8f (95%, 30 h)
F17C8
NH2
Cl
OH
H
O
H
Br
6h (95%, 7 h)
O
O
F17C8
Br
N
4
H
H
O
CO2Me
H
O
H
8g (98%, 5 h)†
8h (94%, 32 h)
8i (96%, 24 h)
6g (83%, 5 h)
6i (93%, 6 h)
*Hantzsch ester ¼ Diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate; †Allowing the reaction to run for 24 h led to partial reduction of C-Br bond.
than 2 or 3 (ref. 21). Although 1, 2 and 3 are calculated to have the 4,4′-di-tert-butyl-2,2′-dipyridyl (dtbbpy) ligand of 3 with
similar reductive abilities in their excited states via oxidative another ppy ligand affording 4, the reduction potentials of the
quenching, only 1 can efficiently produce atom transfer radical catalyst become more negative. Specifically, the reduction potential
addition of CCl4 onto olefins39. On the other hand, by replacing for the Ir3þ ꢀ Ir2þ couple changes from 21.51 V (versus SCE) for
NATURE CHEMISTRY | VOL 4 | OCTOBER 2012 | www.nature.com/naturechemistry
855

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1452
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Table 2 | Reduction of alkenyl iodides and intramolecular reductive cyclizations utilizing Procedure C.
Procedure C
fac-Ir(ppy)3 (2.5 mol%)
Bu3N (10 equiv.)
Procedure C
fac-Ir(ppy)3 (2.5 mol%)
Bu3N (10 equiv.)
R3
R3
I
R1
R1
HCO2H (10 equiv.)
HCO2H (10 equiv.)
or
I
H
MeCN, visible light
MeCN, visible light
R2
R2
H
9a-c
10a-c
9d-j
10d-j
Substrate
Product
Time (h)
60
Yield (%)
Substrate
Product
Time (h)
Yield (%)
BnO
BnO
OMe
OMe
95
8
80†
I
I
H
O
O
9a
10a
H
10f
9f
TBSO
TBSO
60
92
48
71
NTs
NTs
I
H
H
I
10g
9g
9b
10b
OH
OH
2.5
99*
24
63
NTs
NTs
I
H
I
H
10h
9h
9c
10c
I
NTs
5
78
10
86
NTs
O
H
O
I
H
10d
9d
CO2Me
MeO2C
10i
9i
I
I
NTs
15
77
50
60
NTs
H
H
CO2tBu
tBuO2C
10e
9e
10j
9j
*E/Z ratio ¼ 1.3:1; †6.7:1 d.r.
3 to 22.19 V (versus SCE) for 4 and, likewise, the Ir4þ ꢀ Ir3þ
precedent indicating that 4 may be quenched by compounds with
*
couple becomes more negative (20.93 V versus SCE for 3 to reduction potentials that have been measured to be more negative
21.73 V versus SCE for 4)35. The strong reduction potentials of 4 than 22.00 V (versus SCE)45.
prompted our proposal for a novel reductive dehalogenation proto-
col for alkyl, alkenyl and aryl iodides. We realized that the reduction Results and discussion
of unactivated carbon–iodide bonds would be difficult to achieve We began our studies by screening conditions for the reduction
with 4 because of the highly negative reduction potentials typical of 5-iodopentyl benzyl ether (5a), monitoring the conversion by
of alkyl, alkenyl and aryl iodides (for example, the reduction poten- 1H NMR. Based on our protocol for the reductive dehalogenation
tial of s-butyl iodide has been measured to be between 21.61 V and of activated carbon–halogen bonds, we began optimization with
22.10 V versus SCE40,41 and the reduction potential of iodobenzene N,N-diisopropylethylamine and Hantzsch ester in N,N-dimethyl-
has been measured to be between 21.59 V and 22.24 V versus formamide (DMF)46. A survey of solvents revealed that acetonitrile
SCE)42,43. However, our investigation was encouraged by the suc- gave the best conversion over a 24 h reaction time, although
cessful utilization of the oxidative quenching of 4 (ref. 44) by the starting material was not fully consumed, even after
MacMillan and co-workers to form benzyl radicals from electron- increasing the equivalents of N,N-diisopropylethylamine and
deficient benzyl bromides (Fig. 1b)22, as well as by literature Hantzsch ester. Replacing N,N-diisopropylethylamine with other
856
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1452
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a
4.6 mmol (3 g)
fac-Ir(ppy)3 (0.050 mol%)
Hantzsch ester (1.1 equiv.)
Bu3N (2.0 equiv.)
I
H
F17C8
F17C8
OH
OH
MeCN, visible light
10 h, 92%
5h
6h
b
Comparison with batch reaction:
O
O
O
fac-Ir(ppy)3 (0.050 mol%)
HCO2H (5.0 equiv.)
Bu3N (5.0 equiv.)
O
O
O
H
O
fac-Ir(ppy)3 (1.0 mol%)
HCO2H (5.0 equiv.)
Bu3N (5.0 equiv.)
O
MeCN, flow LED
t
R = 40 min, 93%
MeCN, visible light
I
30 h, 95%
7f
8f
I
H
7f
8f
0.020 mmol h−1
30 h
0.900 mmol h−1 (with a 1.33 ml reactor)
t
R = 40 min
Figure 2 | The reduction protocol allows for simultaneous scale-up and lower catalyst loading, and reaction times are shortened when the reaction is run
in a flow reactor. a, Catalyst loading can be decreased to as low as 0.050 mol% without loss of efficiency for a 4.6 mmol (3 g) reaction with substrate 5h,
demonstrating the scalability of these reaction conditions. b, Reaction times are shortened when the reaction is run in a flow reactor, without suffering any
loss in yield. A conversion rate of 0.900 mmol h21 is achieved in the flow reactor, whereas the corresponding batch reaction proceeds at a conversion rate of
0.020 mmol h21
.
a
I
fac-Ir(ppy)3 (2.5 mol%)
I
N
+
9e (75%)
MeCN, visible light
24 h
Ts
N
Ts
9e
11 (14%)
H
b
Oxidized
electron
donor
EtO2C
CO2Et
EtO2C
CO2Et
Electron
donor
N
+
N
H
Ir(ppy)3
Visible
light
H
+
Oxidative
quenching
Pr
R
H
+
Bu2N
Ir(ppy)3+
Bu2N
Pr
+
*
Ir(ppy)3
H-atom
Abstraction
+
CO2
–
R
R3NH•HCO2
R
I
Reaction by-products
Electron/H-atom donors
Figure 3 | Experimental evidence for proposed mechanistic pathway. a, In the absence of an electron donor, substrate 9e forms atom transfer product 11 in
14% yield, indicating the action of the oxidative quenching pathway of fac-Ir(ppy)3. Product 11 arises from short-lived propagation chains initiated by SET from
the excited state of fac-Ir(ppy)3 to the carbon–iodide bond of 9e. b, Proposed mechanistic pathway of photocatalytic radical reductive cleavage of alkyl,
alkenyl and aryl iodides. Through oxidative quenching, visible-light-excited fac-Ir(ppy)3 donates an electron to the carbon–iodide bond and is then reduced to
its ground state by an electron donor. The carbon radical generated undergoes hydrogen atom abstraction to give the reduced product. Possible electron and
hydrogen atom donors are shown, together with their by-products.
reductants, including triethylamine, sodium ascorbate and
Subsequently, we investigated the reactivity of aryl iodides.
1,2-dimethoxybenzene did not improve the conversion. However, Reduction of N-(4-iodophenyl)-4-methylbenzenesulfonamide (7a)
tributylamine exhibited a significant increase in conversion, and was successful with Procedure A; however, the reaction requires
upon exchanging the method of degassing from freeze–pump– 52 h for full consumption of 7a. We attempted to improve the reac-
thaw to argon sparging, full consumption of 5a was achieved in tion efficiency by replacing Hantzsch ester with formic acid, which
24 h (Supplementary Table S1).
is inexpensive and can be easily removed during work-up. To our
The tributylamine and Hantzsch ester combination (Procedure delight, the reduction of 7a was complete in 20 h when 5 equiv. of
A, Methods) was used with several primary and secondary iodides tributylamine and 5 equiv. of formic acid were used. We tested
to give reduction products in good to excellent yields (Table 1). these new conditions (Procedure B, Methods) on several alkyl
This reduction protocol exhibits excellent functional group toler- iodides, but all attempts led to low yields of the desired
ance without affecting benzyl ethers, silyl ethers, acetals, lactones reduced compound. We discovered that the use of Procedure B
or free alcohols. In addition, the chemoselective nature of the leads to a high level of competitive substitution and elimination
reaction allows for the reduction of alkyl iodides in the presence reactions with alkyl iodides that are not observed with Procedure A.
of aryl bromides.
In particular, secondary iodide 5g provided substantial
NATURE CHEMISTRY | VOL 4 | OCTOBER 2012 | www.nature.com/naturechemistry
857

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1452
ARTICLES
elimination product with Procedure B, but was cleanly reduced with fac-Ir(ppy)3 only acts as an initiator for this reaction—there is no
Procedure A. electron donor to effect catalyst turnover and the propagation
Procedure B was applied successfully to a diverse set of aryl chains are short-lived. Hence, we propose that the mechanism of
iodides (Table 1). The buffered reaction conditions were amenable the reaction involves the oxidative quenching of Ir(ppy)3* by the
to both acid and base labile groups, such as carbamates, acetamides alkyl, alkenyl or aryl iodide. Reductive cleavage generates a
and esters. Electron-rich and electron-deficient aryl iodides were all carbon-centred radical that is capable of radical cyclization
cleanly reduced, although electron-rich aryl iodides required longer and/or hydrogen atom abstraction from tributylamine, Hantzsch
reaction times. It is noteworthy that these reaction conditions afford ester orþformate. The catalyst fac-Ir(ppy)3 is regenerated from
the reduction of challenging electron-rich aryl iodides, making this Ir(ppy)3 by oxidation of tributylamine, Hantzsch ester, formate
a general protocol applicable to a wide range of substrates. The reac- or their oxidized forms (Fig. 3b).
tion conditions also make it possible to reduce aryl iodides in the
Conclusion
presence of aryl bromides, aryl chlorides and distal olefins. To
achieve the reduction of unactivated alkenyl iodides (Table 2, sub-
strates 9a–9c) in a reasonable timeframe, increasing the amounts of
tributylamine and formic acid to 10 equiv. (Procedure C, Methods)
was required. Activated alkenyl iodides such as pure Z-9c reduced
very efficiently to produce a diastereomeric mixture of 10c with
an E/Z ratio of 1:0.75 after 2.5 h (Supplementary Fig. S1). In
addition, Procedure C was found to be the most effective for intra-
molecular cyclizations of alkyl, alkenyl and aryl iodide substrates
(Table 2, substrates 9d–9j). Surprisingly, all alkyl iodide substrates
cyclized efficiently without any observable substitution or elimin-
ation products. These radical reductive cyclizations generated a
wide scope of products, including pyrrolidines, tetrahydrofurans,
indoles, indolines, dihydrobenzofurans and carbocycles in moderate
to high yields.
To demonstrate the efficacy of the reduction protocol on a pre-
parative scale, the reduction of 5h (3.0 g, 4.6 mmol) was performed
with lower catalyst loading and reduced amounts of Hantzsch ester.
Gratifyingly, simultaneous scale up of the reaction by 750% and
decrease of the catalyst loading by 2,000% did not cause any signifi-
cant loss of efficiency (Fig. 2a). Furthermore, the reaction time can
be significantly shortened when the reductions are performed
within a flow reactor47. For example, the reduction of 0.60 mmol
of 7f with 1.0 mol% of 4 in a batch reactor required 30 h of light
irradiation to afford 95% yield of 8f (Fig. 2b). However, by utilizing
a 1.33 ml flow reactor with a residence time (tR) of 40 min, the same
scale reduction, employing only 0.050 mol% of 4, only requires a 3 h
reaction time to afford 93% yield of 8f, which indicates a turnover
number (TON) of at least 1,860.
We have developed a visible light photoredox-mediated radical reduc-
tive deiodination protocol capable of reducing alkyl, alkenyl and aryl
iodides. The generated radicals can also undergo intramolecular cycli-
zations to provide a variety of cyclic scaffolds. The reaction protocol is
characterized by mild conditions, low catalyst loading, high yields and
the use of inexpensive and accessible electron and hydrogen atom
donors. Functional group tolerance towards benzyl ethers, silyl
ethers, free alcohols, acetals, lactones, esters, aryl bromides, aryl chlor-
ides, carbamates, distal olefins, sulfonamides, tosylates and aceta-
mides is clearly illustrated. Moreover, the versatility and simplicity
of the reduction protocol allows for easy scale-up, low catalyst
loading and short reaction times when the reaction is run in a flow
reactor. These advances signify the utility of photoredox catalysts in
the area of radical chemistry, which previously has been dominated
by tin, SmI2 and trialkylboranes48.
Methods
Detailed descriptions of experimental and spectroscopic methods and results, as well
as characterization data for all new individual compounds and the 1H and 13C NMR
spectra, are provided in the Supplementary Information.
Procedure A. A flame-dried 10 ml round bottom flask with a rubber septum and
magnetic stir bar was charged with the corresponding alkyl iodide (0.60 mmol,
1.0 equiv.), MeCN (6.0 ml), Hantzsch ester (1.2 mmol, 2.0 equiv.), tributylamine
(1.2 mmol, 2.0 equiv.) and fac-Ir(ppy)3 (0.0060 mmol, 0.010 equiv.). The
heterogeneous mixture was degassed by argon sparging for 30 min and placed in a
250 ml beaker with blue or white light-emitting diodes (LEDs) wrapped inside. The
reaction mixture was stirred at 25–30 8C until it was complete (as judged by thin
layer chromatography (TLC) analysis or gas chromatography-mass spectrometry
(GC-MS)). The solvent was removed from the crude mixture in vacuo and the
residue was dissolved in EtOAc. The contents were poured into a separatory funnel
containing 25 ml of EtOAc and 25 ml of 1 M HCl solution. The layers were
separated and the aqueous layer was extracted with EtOAc (2 × 25 ml). The
combined organic layers were washed with sat. NaHCO3 solution and brine, dried
(Na2SO4) and concentrated in vacuo. The residue was purified by chromatography
on silica gel to afford the desired product.
Mechanism
The successful cyclization of substrates 9d–9j, the more facile
reduction of secondary alkyl iodides in comparison to primary
alkyl iodides, and control reactions that reveal low conversions of
the reduced products in the absence of fac-Ir(ppy)3 and/or visible
light irradiation (Supplementary Table S2) strongly suggest a
radical-based mechanism. In previous work46 we demonstrated
that formic acid/trialkylamine and Hantzsch ester/trialkylamine
combinations are effective electron donor/hydrogen atom donor
systems for the reductive dehalogenation of highly activated
carbon–halogen bonds. The role of these reagents is probably
unchanged for this protocol. However, to ensure that acetonitrile
was not acting as an additional hydrogen atom source, the reaction
of compound 7a was performed in deuterated acetonitrile and no
deuterium incorporation was observed (Supplementary Fig. S2).
Experimental evidence that the reaction was occurring through
the oxidative quenching cycle of 4 was obtained when substrate
9e and 2.5 mol% of fac-Ir(ppy)3 in acetonitrile were subjected to
visible light irradiation for 24 h to produce 14% of atom transfer
product 11 together with 75% of recovered starting material
(Fig. 3a). In the absence of tributylamine and formic acid, neither
reductive quenching of Ir(ppy)3* nor the formation of 10e from 9e
are possible, and oxidative quenching of Ir(ppy)3* leads to an atom
transfer product via cyclization and iodine atom abstraction by
Procedure B. A flame-dried 10 ml round bottom flask with a rubber septum and
magnetic stir bar was charged with the corresponding aryl iodide (0.60 mmol,
1.0 equiv.), MeCN (6.0 ml), tributylamine (3.0 mmol, 5.0 equiv.), formic acid
(3.0 mmol, 5.0 equiv.) and fac-Ir(ppy)3 (0.0060 mmol, 0.010 equiv.). The reaction
mixture was degassed by argon sparging for 30 min and placed in a 250 ml beaker with
blue or white LEDs wrapped inside. The reaction mixture was stirred at 25–30 8C until
it was complete (as judged by TLC analysis or GC-MS). The solvent was removed from
the crude mixture in vacuo and the residue was dissolved in EtOAc. The contents were
poured into a separatory funnel containing 25 ml of EtOAc and 25 ml of 2 M HCl
solution. The layers were separated and the aqueous layer was extracted with EtOAc
(2 × 25 ml). The combined organic layers were washed with sat. NaHCO3 solution and
brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by
chromatography on silica gel to afford the desired product.
Procedure C. A flame-dried 10 ml round bottom flask with a rubber septum and
magnetic stir bar was charged with the corresponding alkenyl iodide or cyclization
substrate (0.60 mmol, 1.0 equiv.), MeCN (6.0 ml), tributylamine (6.0 mmol,
10 equiv.), formic acid (6.0 mmol, 10 equiv.) and fac-Ir(ppy)3 (0.015 mmol,
0.025 equiv.). The reaction mixture was degassed by argon sparging for 30 min and
placed in a 250 ml beaker with blue or white LEDs wrapped inside. The reaction
mixture was stirred at 25–30 8C until it was complete (as judged by TLC analysis or
GC-MS). The solvent was removed from the crude mixture in vacuo and the residue
was dissolved in EtOAc. The contents were poured into a separatory funnel
containing 25 ml of EtOAc and 25 ml of 2 M HCl solution. The layers were
separated and the aqueous layer was extracted with EtOAc (2 × 25 ml). The
the vinyl radical. The low yield of 11 probably occurs because combined organic layers were washed with 2 M HCl solution, sat. NaHCO3 solution
858
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1452
ARTICLES
and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by
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Enantioselective a-benzylation of aldehydes via photoredox organocatalysis.
J. Am. Chem. Soc. 132, 13600–13603 (2010).
Received 26 March 2012; accepted 8 August 2012;
published online 24 September 2012
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Acknowledgements
The authors acknowledge financial support for this research from the NSF (CHE-1056568),
the Alfred P. Sloan Foundation, Amgen and Boehringer Ingelheim. J.D.N. thanks
AstraZeneca for a graduate fellowship and E.M.D. thanks the Boston University
Undergraduate Research Program for research support. NMR (CHE-0619339) and mass
spectrometry (CHE-0443618) facilities at Boston University are supported by the NSF.
The authors thank J.W. Tucker for experimental assistance.
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Author contributions
J.D.N., E.M.D. and J.M.R.N. performed the experiments. All authors conceived and
designed the experiments, analysed the data, contributed to discussions and wrote
the manuscript.
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permission information is available online at
http://www.nature.com/reprints. Correspondence and requests for materials should be
addressed to C.R.J.S.
Competing financial interests
The authors declare no competing financial interests.
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