Electron-transfer photoredox catalysis: Development of a tin-free reductive dehalogenation reaction

Article abstract of DOI:10.1021/ja9033582

(Chemical Equation Presented) We report an operationally simple, tin-free reductive dehalogenation system utilizing the well-known visible-light-activated photoredox catalyst Ru(bpy)₃Cl₂ in combination with ⁱPr₂

Full text of DOI:10.1021/ja9033582

Published on Web 06/05/2009
Electron-Transfer Photoredox Catalysis: Development of a Tin-Free Reductive
Dehalogenation Reaction
Jagan M. R. Narayanam, Joseph W. Tucker, and Corey R. J. Stephenson*
Department of Chemistry, Boston UniVersity, Boston, Massachusetts 02215
Received April 25, 2009; E-mail: crjsteph@bu.edu
Table 1. Optimization of the Reductive Debromination of 1a
The use of visible light as a promoter in synthesis is appealing
because of its natural abundance, ease of use, and potential
application on an industrial scale.1 However, the lack of visible-
light absorption by many organic molecules has limited the number
of applications documented to date. A solution to this problem
involves the use of photosensitive catalysts.2 Recent efforts from
the MacMillan3a and Yoon3b laboratories have focused on the use
of the well-known photoredox catalyst tris(2,2′-bipyridyl)ruthe-
nium(II) chloride, Ru(bpy)3Cl2,4 to promote the enantioselective
alkylation of aldehydes and [2 + 2] cycloaddition reactions,
respectively. In this paper, we describe an environmentally benign,5
tin-free reductive dehalogenation6 system that is based on the
combination of Ru(bpy)3Cl2 and an amine as the hydrogen atom
source. In addition, this photoredox system gives superior chemose-
lectivity compared with traditional methodologies based on the
chemistry of radicals. Furthermore, photoredox catalysis is presented
as a potential means of accessing traditional radical chemistry while
avoiding the toxicity and purification problems associated with tin
hydrides (Scheme 1).7-9
entry
conditions
yield (%)a
1
2
3
4
5
6
iPr2NEt (2 equiv), HCOOH (2 equiv), Ru2+ (5 mol %), 24 h
iPr2NEt (10 equiv), HCOOH (10 equiv), Ru2+ (2.5 mol %), 4 h
Et3N (10 equiv), HCOOH (10 equiv), Ru2+ (5 mol %), 24 h
iPr2NEt (2 equiv), 3 (1.1 equiv), Ru2+ (2.5 mol %), 4 h
25
90
20
95
90
75
b
iPr2NEt (10 equiv), HCOOH (10 equiv), Ru2+ (1 mol %), 4 h
iPr2NEt (10 equiv), HCOOH (10 equiv), Ru2+ (0.05 mol %), 4 h
c
a Isolated yield after purification by chromatography on SiO2. b 25%
conversion. c Reaction conducted on a 2.0 g (4.6 mmol) scale.
The scope of this process is illustrated by the examples detailed
in Table 2. Utilizing our optimized conditions, we were able to
successfully reduce both C-Br and C-Cl bonds in the presence
of other functional groups such as free hydroxyls (entries 4 and 6),
olefins (entry 9), and alkynes (entry 10). Furthermore, we found
excellent selectivity for the reductive dehalogenation of alkyl
bromides and chlorides R to electron-withdrawing groups over vinyl
iodides (entry 9) and aryl bromides and iodides (entries 2, 3, 7,
and 8). These conditions were also tolerant of protecting groups,
including silyl ethers (entry 5) and carbamates (entries 1-3). In
the case of less reactive chlorinated compounds, SN2 substitution
by the formate ion was competitive with the dehalogenation
reaction. For these substrates, the simple substitution of 3 in place
of formic acid as the hydrogen atom source provided a comple-
mentary set of reaction conditions for the R-chlorocarbonyl
compounds (entries 7-10). Furthermore, reduction of simple alkyl
halides was not observed.14
Scheme 1. Photoredox Catalytic Reduction and Potential C-C
Bond Formation
Throughout our investigations, we conducted a series of control
experiments using 1a as a representative substrate. Exclusion of
any of the reaction components, including visible light, Ru(bpy)3Cl2,
iPr2NEt, or combinations thereof, afforded only trace amounts of
the reduced product 2a after 48 h. Furthermore, to add credence to
the intermediacy of a radical, we utilized an R-bromo-R-cyclopropyl
imide substrate as a radical clock (eq 1):15 The corresponding
Our preliminary studies focused on the reductive debromina-
tion of bromopyrroloindoline 1a.10,11 Initial success was obtained
upon subjecting 1a to irradiation by a 14 W fluorescent lamp12
with Ru(bpy)3Cl2 (5 mol %) as a catalyst in the presence of
iPr2NEt (2 equiv) in DMF for 24 h.13 These conditions provided
the reduced product in 25% yield (40% conversion). Subsequent
optimization revealed two sets of conditions of broad utility for
reductive debromination: Ru(bpy)3Cl2 (2.5 mol %) in DMF with
(a) iPr2NEt (10 equiv) and formic acid (10 equiv) or (b) iPr2NEt
(2 equiv) and Hantzsch ester (3) (1.1 equiv). In the case of 1a,
both systems cleanly produced the debrominated product in
>90% yield. In addition, lower catalyst loading had little effect
on the reaction: catalyst loadings as low as 0.05 mol % gave
efficient reductive dehalogenation without prolonging the reac-
tion time (Table 1).
cyclopropyl ring fragmentation product was obtained in 52%
isolated yield. This result strongly suggests that the reaction
proceeds via a radical mechanism.
To further support our mechanistic hypothesis, we performed
labeling studies using either DCO2D or DCO2H (98% D, 10 equiv)
with iPr2NEt (10 equiv) and Ru(bpy)3Cl2 (2.5 mol %) in DMF for
the reduction of 1a (eq 2):16 Both afforded a 2aH/2aD product ratio
9
8756 J. AM. CHEM. SOC. 2009, 131, 8756–8757
10.1021/ja9033582 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reductive Dehalogenation Using Photoredox Catalysis
Scheme 2. Plausible Mechanism for the Reductive Dehalogenation
In conclusion, we have developed a catalytic, tin-free method
for reductive dehalogenation utilizing visible-light photocatalysis.
The reaction is highlighted by its chemoselectivity, affording the
reduced compounds in high yields under mild reaction conditions.
Further development and application of photoredox catalysis in the
context of radical chemistry and its application to C-C bond-
forming reactions are currently underway.
Acknowledgment. This work was supported by startup funds
from Boston University. J.M.R.N. thanks the Swiss National
Science Foundation for a postdoctoral fellowship. The authors thank
Cambridge Isotope Laboratories for a gift of Et3N-d15.
Supporting Information Available: Experimental procedures and
1H and 13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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a Isolated yield after purification by chromatography on SiO2.
b Ru(bpy)3Cl2 ·6H2O (2.5 mol %), iPr2NEt (10 equiv), HCO2H (10
c
i
equiv), DMF, hν, r.t., 4 h. Ru(bpy)3Cl2 ·6H2O (2.5 mol %), Pr2NEt (2
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hydrogen atom source in the reduction. In addition, no deuterium
incorporation was observed in 2a when the reduction reaction was
conducted in DMF-d7.
We also performed a reaction using formic acid (10 equiv), Et3N-
d15 (10 equiv), and Ru(bpy)3Cl2 (2.5 mol %) in DMF, which led to
only 25% conversion of starting material over 24 h and no
incorporation of deuterium into the reduced product 2a. This
suggests that in the absence of Pr2NEt, the formate ion can
successfully compete with the triethylammonium radical cation as
the major hydrogen atom source (Scheme 2, Path A).
Accordingly, we propose a mechanism wherein single-electron
transfer from the ammonium formate complex to the excited Ru(II)*
occurs, forming Ru(I) and the radical cation of the complex.
Reduction of the carbon-halogen bond by the electron-rich Ru(I)
forms the alkyl radical, which can be reduced by abstraction of a
hydrogen atom from one of the methine carbons of the radical cation
of iPr2NEt (Scheme 2, Path B). The proposed hydrogen abstraction
i
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(15) (a) Newcomb, M. Tetrahedron 1993, 49, 1151. (b) Griller, D.; Ingold, K. U.
Acc. Chem. Res. 1980, 13, 317.
i
from the radical cation of Pr2NEt also accounts for the reductive
dehalogenation of 1a by 3° amines alone in the presence of
(16) See the Supporting Information for details.
Ru(bpy)3Cl2.
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