Activation of C-H bonds via the merger of photoredox and organocatalysis: A coupling of benzylic ethers with schiff bases

Article abstract of DOI:10.1021/ja5102695

The photoredox-mediated coupling of benzylic ethers with Schiff bases has been accomplished. Direct benzylic C-H activation by a combination of a thiol catalyst with an iridium photocatalyst and subsequent radical-radical coupling with secondary aldimines

Full text of DOI:10.1021/ja5102695

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Communication
Activation of C–H Bonds via the Merger of Photoredox and
Organocatalysis: A Coupling of Benzylic Ethers with Schiff Bases
Dominik Hager, and David W. C. MacMillan
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 17 Nov 2014
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Activation of C–H Bonds via the Merger of Photoredox and Organocatalysis:
A Coupling of Benzylic Ethers with Schiff Bases
Dominik Hager and David W. C. MacMillan*
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, USA
dmacmill@princeton.edu
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RECEIVED DATE
Physical properties that enable thiol-photo C–H activation
Abstract: The photoredox-mediated coupling of benzylic ethers
with Schiff bases has been accomplished. Direct benzylic C−H
activation by a combination of a thiol catalyst with an iridium
photocatalyst and subsequent radical–radical coupling with
secondary aldimines affords a variety of β-amino ether products
in good to excellent yields. Mechanistic studies suggest that a
reductive quenching pathway of the photocatalyst is operable. In
addition, the photon dependence of the reaction was
demonstrated by modulation of the illuminated surface area.
H
H
S
COOMe
OMe
H
C–H BDE = 85.8 kcal/mol
S–H BDE = 87.2 kcal/mol
weak C–H bonds: activationvia bond energies, H atom transfer
e–
base
proton-coupled
electron transfer
H
S
O
O
3
The direct and controlled C−H functionalization of sp -
hybridized carbons has become a challenging goal in modern
synthetic organic chemistry. In this context, our laboratory has
recently introduced a protocol that allows the activation and
III
+
S
*
Ir (ppy) (dtbbpy)
2
OMe
OMe
thiol cat.
(PCET)
1
redox cat.
thiyl radical
photoinduced
oxidized with –H+
activation mode
subsequent arylation of benzylic C−H bonds via the cooperative
action of a photoredox catalyst and a thiol organocatalyst (Eq
2
Direct arylation of benzylic ethers with cyanoaromatics (Eq 1)
1).
This transformation relies on the coupling of two
catalytically generated radicals: an arene radical anion formed by
reduction of an arylnitrile, and a benzyl ether radical generated
by thiyl-mediated hydrogen atom abstraction from benzylic
ethers. Moreover, we postulate that the thiol organocatalyst
CN
OMe
OMe
photoredox catalyst
3
CN
undergoes oxidative proton-coupled electron transfer (PCET) in
thiol catalyst
CN
the presence of photoexcited catalysts to generate the requisite
benzylic ether
arylated ether
4
thiyl radical that can selectively cleave the C–H bond of
5
benzylic ethers.
This photoredox–organocatalysis C–H
Merger of benzylic ethers with Schiff bases via photoredox (Eq 2)
functionalization mechanism exploits several established
6
physical properties (e.g. bond dissociation energies (BDEs),
Ph
2
7
Ph
N
Ph
hydrogen-atom transfer exchange constants, and oxidation
N
NH
potentials) that are predictable across a wide range of reaction
classes. Herein we translate this general C–H functionalization
concept to the direct coupling of benzyl ethers with secondary
aldimines to afford β-amino ethers in one step (Eq 2). This new
radical–radical coupling protocol employs readily available
substrates, a visible light source, and the combination of a thiol
catalyst and photocatalyst.
OMe
photoredox
catalyst
OMe
OMe
thiol
catalyst
β-amino ether
(racemic)
1
The β-amino ether functionality is a widespread motif in
synthetic organic chemistry. However, the synthesis of these
structural units is often challenging and typically requires
multiple steps, organometallic reagents and immoderate reaction
radical 1 (via oxidation) and α-amino radical anion 2 (via
reduction) prior to a critical hetero-coupling of these two high-
energy species (Eq 2). Importantly, this new multi-catalysis
reaction mechanism would be organocatalytic, redox-neutral, as
well as atom-economical and should provide an unprecedented
and non-classical C–C disconnection that will find utility in the
fields of medicinal chemistry and organic molecule construction.
Design Plan. The proposed catalytic cycle of our new light-
8
conditions. With this in mind, we recently hypothesized that a
one-step C–C bond coupling of benzylic ether radicals and an α-
amino radical would allow direct access to this important
synthon using simple and mild reagents and catalysts. Seminal
studies of Roberts in the 1990s demonstrated that electrophilic
thiyl radicals are excellent systems to abstract H from aldehydes
to generate acyl radicals. We recently demonstrated that similar
10
driven redox transformation is depicted in Scheme 1. It has
•
long been established that the photoredox catalyst
9
III
III
Ir (ppy) (dtbbpy)PF (3) will be photoexcited to the *Ir state 4
3
6
open-shell thiyl species, generated via proton-coupled electron
by visible light irradiation with a household light bulb or blue
LEDs. Excited species 4 can function as an oxidant (E
+0.66 V vs. SCE in MeCN) and can be quenched by the thiol
2
*
III/II
transfer, are superior catalysts that generate α–oxy radicals.
=
1
/2
1
1
With this in mind, we questioned whether photoredox catalysis
II
would allow the concurrent generation of α-benzylic ether
catalyst methyl thioglycolate (6) to produce Ir (ppy) (dtbbpy)
2
(
5), as well as thiyl radical 7.
1
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Scheme 1. Proposed Mechanism of the Heterocoupling Reaction.
Table 1. Initial Studies and Reaction Optimization.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
OMe
OMe
NPh
1 mol% photocat
OMe
household
Ar
20 mol% thiol 6
N
light source
N-aryl imine 8
additive,
solvent, 23 °C
light source
HN
R
H
MeO
Ph
IrIII(ppy)2(dtbbpy)+ (3)
Imine coupling partner
ether
imine 12
β-amino ether (racemic)
catalyst
entry
photocatalyst
additive
light source
solvent yielda
SET
Ar
Photoredox
Cycle
9
–
N
1
2
3
4
5
6
7
8
9
Ir(ppy)3
K HPO (10 mol%)
26 W CFL
26 W CFL
26 W CFL
blue LEDs
blue LEDs
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
MeCN
DMSO
DMA
DMA
DMA
0%
0%
IrIII(ppy)2(dtbbpy)+ (4)
2
4
*
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
oxidant
Ru(bpy) Cl
K HPO (10 mol%)
R
3
2
2
2
2
4
4
4
IrII(ppy)2(dtbbpy) (5)
Ir(ppy)
2
(dtbbpy)PF
(dtbbpy)PF
6
6
6
6
6
6
K
K
HPO
HPO
(10 mol%)
(10 mol%)
42%
75%
55%
22%
83%
83%
83%
73%
70%
0%
Radical–
reductant
Ir(ppy)
2
Radical
PCET
Ir(ppy) (dtbbpy)PF
none
2
Coupling
Ir(ppy)
Ir(ppy) (dtbbpy)PF
(dtbbpy)PF
n-Bu
NOAc (10 mol%) blue LEDs
n-Bu NOAc (0.2 mol%) blue LEDs
2
4
OPG
MeOOC
SH
–
H+
thiol catalyst 6
2
4
Ir(ppy)
(dtbbpy)PF
LiOAc (0.2 mol%)
LiOAc (10 mol%)
LiOAc (10 mol%)
LiOAc (10 mol%)
LiOAc (10 mol%)
LiOAc (10 mol%)
LiOAc (10 mol%)
blue LEDs
blue LEDs
blue LEDs
blue LEDs
none
2
Organocatalytic
Cycle
11
Ir(ppy)
Ir(ppy)
Ir(ppy)
Ir(ppy)
(dtbbpy)PF
6
2
1
0
1
2
2
2
(dtbbpy)PF
(dtbbpy)PF
(dtbbpy)PF
6
HAT
+
H+
S
COOMe
1
6
6
6
thiyl radical 7
12
3b
Ir(ppy) (dtbbpy)PF
blue LEDs
blue LEDs
0%
1
2
OPG
R
H
N
14
none
0%
Ar
OPG
H
benzyl ether
substrate
a
1
Yield determined by
H
NMR analysis using 1-bromo-3,5-bis-
b
(trifluoromethyl)benzene as internal standard. Reaction performed in the absence
of methyl thioglycolate. CFL = Compact Fluorescent Light.
1
0
β-amino ether (racemic)
radical coupling was further improved by irradiating the
photocatalyst 3 (λmax = 460 nm) with light adjusted to the
catalyst’s absorption maximum via the implementation of blue
LEDs (entry 4, 75% yield). Next, we determined that the base
additive had a significant influence on the reaction outcome.
More specifically, while the lack of a basic additive resulted in a
moderate yield (entry 5, 55% yield), we found that the use of the
soluble n-Bu NOAc base in trace quantities provided a
significant improvement (entry 7, 0.2 mol%, 83% yield).
Notably, the use of n-Bu NOAc at the 10 mol% level (entry 6)
resulted in diminished yields (22% yield). These results are
consistent with the requirement of a soluble base that enables a
concerted PCET mechanism for the formation of thiyl radical 7
(Scheme 1). We recognize that a stepwise pathway may also be
operable, wherein deprotonation of the thiol catalyst could
precede the oxidation of the resulting thiolate anion (mechanistic
studies are ongoing to delineate between these two pathways).
As an effective alternative to the hygroscopic n-Bu NOAc, we
have established LiOAc (entry 8) as a more operationally
convenient additive at 10 mol% loading (entry 9). In addition,
we have found that DMA is the superior medium for this process
while solvents such as MeCN or DMSO are also competent
(entries 10 and 11, 73% and 70% yield). Finally, control
experiments verified the requirement of light, organocatalyst,
and photocatalyst, as no product was observed in the absence of
these components (entries 12–14).
Reaction Scope. With the optimal coupling conditions in
hand, we next sought to determine the scope of aldimines that
can be employed in this new radical–radical heterocoupling
protocol. As shown in Table 2, electronically ‘neutral’ imines
(entry 1, 77% yield), as well as electron-rich arenes increase the
overall coupling efficiency (entries 2–4, 79–85% yield). We
rationalized that electron-rich α-amino radicals are more
nucleophilic and thereby more rapidly react with benzylic radical
11, resulting in generally higher yields. In addition, bicyclic
arenes, such as naphthalene (entry 5, 85%), and the
heteroaromatic quinoline (entry 6, 58%) are well tolerated. With
Although the oxidation potential of typical thiols (E = +0.85 V
1
/2
1
2
vs. SCE for cysteine) should render this electron transfer
unfavorable, we expect that the addition of a weakly basic
additive (K HPO or LiOAc) would facilitate the formation of
2
4
thiyl radical 7 via a concerted PCET event. In order to close the
II
III/II
11
photoredox cycle, Ir species 5 (E1/2
= –1.51 V vs. SCE)
4
red
should be able to reduce the N-aryl imine 8 (E
= –1.98 V vs.
1
/2
13
SCE for R = Ar = Ph) under the reaction conditions via a
single-electron transfer (SET) event to afford the α-amino
radical anion 9. With respect to BDEs, thiyl radical 7 should
readily abstract a hydrogen atom from benzyl ether substrate 10
4
1
4
(α-C–H BDE = 85.8 kcal/mol for benzyl methyl ether) in a
hydrogen atom transfer (HAT) process to regenerate the thiol
catalyst 6 (S–H BDE = 87.2 kcal/mol) and to complete the
organocatalytic cycle. We assume the resulting benzylic radical
1
5
1
1 will rapidly combine with α-amino radical anion 9 to afford
4
the desired β-amino ether product. This critical carbon–carbon
bond-forming step should be facilitated by the persistent radical
effect, wherein species 9 is a long-lived open shell species that
does not readily homo-dimerize, thereby enabling a highly
17
1
6
selective radical–radical heterocoupling event.
Although a
radical–radical coupling is proposed we are aware that an
addition of benzylic radical 11 into imine 8 followed by
reduction of the N–centered radical is also feasible. However,
we consider this pathway as unlikely since imine dimer and
imine reduction byproducts have been observed in certain cases.
Results. The proposed ether–imine coupling was first
evaluated with a series of established photoredox catalysts
Table 1). Initially we found that irradiation of benzyl methyl
ether, imine 12, methyl thioglycolate (6), and K HPO with
visible light in the presence of Ir(ppy) or Ru(bpy) Cl resulted
(
2
4
3
3
2
in no observable yield of the desired 1,2-amino ether product
entries 1 and 2). Fortunately, however, use of the heteroleptic
catalyst Ir(ppy) (dtbbpy)PF (3) provided the desired β-amino
(
2
6
ether in 42% yield (entry 3). The efficiency of this hetero-
2
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Journal of the American Chemical Society
a
a
Table 2. Scope of the Imine Coupling Partner.
Table 3. Scope of the Ether Coupling Partner.
1
2
3
4
5
6
7
8
9
X
O
Y
Y
Y
1
mol%
1 mol%
X
N
O
N
Ir(ppy)2(dtbbpy)PF6
X
Ir(ppy)2(dtbbpy)PF6
Ar
NH
Ph
OMe
HN
Ar
20 mol% thiol cat. 6
10 mol% LiOAc
2
0 mol% thiol cat. 6
0 mol% LiOAc
Y
X
1
Ph
OMe
DMA, blue LEDs
ether
imine
DMA, blue LEDs
ether
imine
β-amino ether
β-amino ether
1
3
5
7
9
2
1
2
Me
OMe
HN
OMe
H
N
H
N
MeO
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
HN
Ph
Ph
OMe
Ph
OMe
MeO
Ph
(
(
(
±)-13 77% yield
(±)-14 79% yield
(±)-27 85% yield
(±)-28 73% yield
4
3
4
MeO
MeO
OMe
Me
OMe
HN
Me
OMe
H
N
H
N
MeO
HN
Ph
Ph
OMe
Ph
OMe
Ph
±)-15 81% yield
(±)-16 85% yield
(±)-29 76% yield
(±)-30 82% yield
6
5
6
N
OBn
OTBS
H
N
H
N
HN
Ph
HN
Ph
Ph
OMe
Ph
OMe
±)-17 85% yield
(±)-18 58% yield
(±)-31 73% yield
(±)-32 70% yield
8
7
8
OTBS
HN
OTIPS
HN
H
N
H
N
Ph
(
OMe
OMe
Ph
OMe
COOMe
MeO
Ph
MeO
Ph
±)-19 61% yield
(±)-20 56% yield
(±)-33 80% yield
(±)-34 82% yield
10
9
10
MeO
MeO
OMe
O
O
H
N
H
N
HN
Ph
HN
Ph
Ph
OMe
Br
Ph
OMe
F
(
±)-21 84% yield
(±)-22 84% yield
(±)-35 62% yield
(±)-36 66% yield
1
1
12
11
12
3
F C
O
OTBS
HN
H
N
H
N
HN
Ph
Ph
OMe
Ph
OMe
N
Br
N
Ph
(
±)-23 75% yield
(±)-24 66% yield
(±)-38 54% yieldb
(±)-37 75% yield
1
3
14
13
14
MeO
N
OTBS
O
OTBS
S
H
N
H
N
HN
Ph
HN
Ph
Ph
OMe
Ph
OMe
N
(±)-25 58% yield
(±)-26 73% yield
±)-39 45% yieldb
(±)-40 53% yieldb
(
a
Isolated yields, see Supporting Information for experimental1 details.
Diastereomeric ratios (d.r.) between 1.1:1 and 1.4:1, determined by H NMR
analysis.
a
Isolated yields, see Supporting Information for experimental details.
1
Diastereomeric ratios between 1:1 and 1.5:1, determined by H NMR analysis.
b
Reaction performed with 10 equiv. of aromatic ether.
respect to the aniline-derived moiety of the imine, we found that
strongly electron-donating and -withdrawing groups have a
deleterious effect on overall reaction yield (entries 7 and 8, 61%
and 56% yield); however, high efficiency is achieved when
halogen atoms are introduced at the para-positions (entries 9 and
10, both 84% yield). Moreover, aldimines that incorporate a CF3
group or pyridine-based heteroaromatics were found to be viable
coupling partners for this redox process (entries 11–14, 58–75%
yield).
Next we focused on expanding the range of benzylic ethers in
this dual catalysis protocol (Table 3). To our delight we found
that electron-rich ethers give the desired products in high yield
(entry 1, 85% yield), along with para-, meta-, and ortho-
3
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substituted arenes (entry 1–4, 73–85% yield). With respect to
activation of the ether or imine coupling partner. Stern–Volmer
quenching experiments strongly suggest that reductive
quenching pathway is operative. Furthermore, the reaction rate
was investigated with respect to the illumination surface area,
revealing that the transformation is photon-limited under the
typical reaction conditions.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the potential for broad application, it is important to recognize
that a variety of protecting groups are well tolerated in this
carbon–carbon bond forming process (entries 5–8, 70–82%
a
yield).
Moreover, cyclic ethers such as phthalane and
isochromane are useful substrates, further demonstrating the
versatility of this photoredox reaction (entries 9–11, 62–75%
yield). Perhaps most notably, a wide range of heteroaromatic-
containing ethers can be readily implemented using these
reaction conditions (entries 12–14, 45–54% yield), an important
consideration with respect to medicinal chemistry applications.
During the course of these studies, we rationalized that the
rate of the reaction is likely dependent on the number of photons
penetrating the reaction vessel and is therefore dependent on the
illumination surface area. Thus, we investigated the progress of
this transformation with respect to the size and nature of the
Acknowledgement.ꢀ ꢀ Financial support was provided by
NIHGMS (R01 GM103558-03) and kind gifts from Merck and
Amgen. D. H. is grateful for financial support from the German
Research Foundation (DFG).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Supporting Information Available. Experimental procedures
and spectral data are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
7
reaction containers employed. It was shown that the typical
reaction with N-phenyl imine 12 and benzyl methyl ether was
slowest (22 h) in a standard reaction vial (as used in Tables 1–3).
Indeed, when the same transformation was conducted in an
NMR tube, the reaction proceeded with a significantly faster
reaction rate with complete product formation determined at 14
hours. However, the fastest protocol we have achieved thus far
for this β-amino ether formation (6 hours to completion) has
been accomplished by maximizing the surface area via the use of
References
(
1) (a) Bergman, R. G. Nature 2007, 446, 391. (b) Godula, K.; Sames, D. Science
006, 312, 67. (c) Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507.
2
(2) Qvortrup, K.; Rankic, D. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2014,
136, 626.
(
3) (a) Mayer, J. M. Annu. Rev. Phys. Chem. 2004, 55, 363. (b) Huynh, M. H. V.;
Meyer, T. J. Chem. Rev. 2007, 107, 5004. (c) Warren, J. J.; Tronic, T. A.;
Mayer, J. M. Chem. Rev. 2010, 110, 6961.
(4) (a) Tyson, E. L.; Ament, M. S.; Yoon, T. P. J. Org. Chem. 2013, 78, 2046. (b)
Nguyen, T. M.; Manohar, N.; Nicewicz, D. A. Angew. Chem. Int. Ed. 2014,
53, 6198. (c) DeForest, C. A.; Anseth, K. S. Angew. Chem. Int. Ed. 2012, 51,
1
8
PFA tubing as a reaction vessel.
These results clearly
1
816.
demonstrate (i) that this transformation as currently performed is
photon-limited with respect to overall rate and (ii) it will likely
be well suited to reaction scale up via flow protocols.
(5) For some related examples on thiyl mediated hydrogen atom abstraction
catalysis in organic synthesis, see: Feray, L.; Kuznetsov, N.; Renaud, P. In
Radicals in Organic Synthesis, Vol. 2; Renaud, P.; Sibi M. P., Eds.; Wiley-
VCH: Weinheim, 2001; p. 256 and references therein.
Last, to provide further mechanistic insight into the pathway
of this new photoredox coupling, we have conducted a series of
(
6) Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic Compounds;
CRC Press LLC: Boca Raton, FL, 2003.
(7) Mayer, J. M. Acc. Chem. Res. 2011, 44, 36.
1
9
Stern–Volmer quenching studies with Ir(ppy) (dtbbpy)PF (3),
2
6
(
8) (a) Arrasate, S.; Lete, E.; Sotomayor, N. Tetrahedron: Asymmetry 2002, 13,
311. (b) Bergmeier, S. C. Tetrahedron 2000, 56, 2561. (c) Reddy, K. S.; Solà,
L.; Moyano, A.; Pericàs, M. A.; Riera, A. J. Org. Chem. 1999, 64, 3969. (d)
Cho, G. Y.; Ko, S. Y. J. Org. Chem. 1999, 64, 8745.
2
0
benzalaniline, butyl thioglycolate (41), and n-Bu NOAc as a
4
2
1
soluble additive. As shown in Figure 1, these investigations
clearly demonstrate the thiol catalyst 41 can indeed quench the
excited photocatalyst, but only in the presence of the acetate base
(9) (a) Roberts, B. P. Chem. Soc. Rev. 1999, 28, 25. (b) Dang, H.-S.; Roberts, B.
P. J. Chem. Soc., Perkin Trans. 1 1998, 67. (c) Dang, H.-S.; Roberts, B. P.
Tetrahedron Lett. 1999, 404, 8929.
(10) (a) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77. (b) Nagib,
D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131,
(
no quenching was observed by the thiol in the absence of
acetate). In addition, benzalaniline quenches the excited
1
9
photocatalyst only to a minor extent, suggesting that a
reductive quenching of the photocatalyst is operable as the
predominant pathway.
1
0875. (c) Shih, H.-W.; Vander Wal, M. N.; Grange, R. L.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2010, 132, 13600. (d) McNally, A.; Prier, C. K.;
MacMillan, D. W. C. Science 2011, 334, 1114. (e) Nagib, D. A.; MacMillan,
D. W. C. Nature 2011, 480, 224. (f) Rono, L. J.; Yayla, H. G.; Wang, D. Y.;
Armstrong, M. F.; Knowles, R. R. J. Am. Chem. Soc. 2013, 135, 17735.
(11) Slinker, J. D.; Gorodetsky, A. A.; Lowry, M. S.; Wang, J. Parker, S.; Rohl, R.;
Bernhard, S.; Malliaras, G. G. J. Am. Chem. Soc. 2004, 126, 2763.
70
HS
HS
COOBu
COOBu
+
4
n-Bu NOAc
(
12) Shaidarova, L. G.; Ziganshina, S.-A.; Budnikov, G. K. J. Anal. Chem. 2003,
58, 640.
6
5
4
3
0
0
0
0
(13) Root, D. K.; Smith W. H. J. Electrochem. Soc. 1982, 129, 1231.
(
14) Ochiai, M.; Yamane, S.; Hoque, M. M.; Saito, M.; Miyamoto, K. Chem.
Commun. 2012, 48, 5280.
(15) Escoubet, S.; Gastaldi, G.; Vanthuyne, N.; Gil. G.; Siri, D.; Bertrand M. P. J.
Org. Chem. 2006, 71, 7288.
I /I
0
(
16) (a) Studer, A. Chem. Eur. J. 2001, 7, 1159. (b) Studer, A. Chem. Soc. Rev.
2004, 33, 267. (c) Fischer, H. J. Am. Chem. Soc. 1986, 108, 3925. (d) Rüegge,
D.; Fischer, H. Int. J. Chem. Kinet. 1989, 21, 703. (e) Kothe, T.; Marque, S.;
Martschke, R.; Popov, M.; Fischer, H. J. Chem. Soc., Perkin Trans. 2 1998,
1553.
20
1
0
0
(17) See Supporting Information for experimental details.
(
18) Nguyen, J. D.; Reiß, B.; Dai, C.; Stephenson, C. R. J. Chem. Commun. 2013,
9, 4352.
4
(
(
19) See Supporting Information for fluorescence quenching experiments.
20) Due to an easier handling, butyl thioglycolate (41) was the preferred reagent
in Stern–Volmer studies.
0.00
0.01
0.02
0.03
0.04
Quencher concentration (M)
(21) In contrast to LiOAc, n-Bu
4
NOAc is fully soluble in DMA and was therefore
Figure 1. Stern–Volmer quenching studies with butyl thioglycolate
41) and n-Bu NOAc.
applied in Stern–Volmer studies.
(
4
In summary, we have developed a new photoredox protocol
that allows the direct coupling of benzylic ethers with Schiff
bases to afford β-amino ether adducts. This general and mild
carbon–carbon bond formation tolerates a variety of different
functionalities and protecting groups. Notably, this C–H bond
functionalization method is redox neutral and requires no pre-
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