Merging Photochemistry with Electrochemistry: Functional-Group Tolerant Electrochemical Amination of C(sp3)?H Bonds

Article abstract of DOI:10.1002/anie.201813960

Direct amination of C(sp³)?H bonds is of broad interest in the realm of C?H functionalization because of the prevalence of nitrogen heterocycles and amines in pharmaceuticals and natural products. Reported here is a combined electrochemical/pho

Full text of DOI:10.1002/anie.201813960

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Accepted Article
Title: Merging Photochemistry with Electrochemistry: Functional Group
Tolerant Electrochemical Amination of sp³ C–H Bonds
Authors: Fei Wang and Shannon S Stahl
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10.1002/anie.201813960
Angewandte Chemie International Edition
COMMUNICATION
Merging Photochemistry with Electrochemistry: Functional Group
Tolerant Electrochemical Amination of sp3 C–H Bonds
Fei Wang and Shannon S. Stahl*
Abstract: Direct amination of sp3 C–H bonds is of broad interest in
the realm of C–H functionalization because of the prevalence of
nitrogen heterocycles and amines in pharmaceuticals and natural
products. Here, we report a combined electrochemical/photochemical
method for dehydrogenative C(sp3)–H/N–H coupling that exhibits
good reactivity with both sp2 and sp3 N–H bonds. The results show
how use of iodide as an electrochemical mediator, in combination with
light-induced cleavage of intermediate N–I bonds, enables the
electrochemical process to proceed at low electrode potentials. This
approach significantly improves the functional-group compatibility of
electrochemical C–H amination, for example, tolerating electron-rich
aromatic groups that undergo deleterious side reactions in the
presence of high electrode potentials.
compounds, both of which compromise the atom-economy and
other appealing features of these methods. Several distinct
mechanistic approaches have been investigated in these
electrochemical HLF-type reactions: (i) stepwise ET-PT-ET to
generate a benzyl cation, which reacts with an appended nitrogen
nucleophile,[12 ] (ii) proton-coupled electron transfer (PCET) to
generate a nitrogen-centered radical that promotes 1,5-HAT,
similar to the key C–H activation step in the HLF reaction,[13] and
(iii) bromide-mediated formation of an N-bromo intermediate that
undergoes thermal N–Br homolysis to achieve the key 1,5-HAT
step.[14 , 15 ] Each of these examples exhibits limited functional
group compatibility, owing to the requirement for high anode
potentials (Figure 1B). These issues could be addressed by using
a mediator that undergoes regeneration at lower potentials. A
number of modified-HLF reactions have been reported with
stoichiometric chemical oxidants, catalytic I2, and visible light
illumination,[11] raising the possibility that iodide could be used as
Synthetic methods for electrochemical oxidation of organic
molecules are the focus of rapidly increasing interest.[1,2] Such
reactions are appealing because protons are often effective as
the terminal oxidant, resulting in the generation of H2 as the sole
stoichiometric byproduct. Important challenges, however, must be
overcome to expand the utility of these methods. For example,
high electrode potentials required to initiate electron transfer from
an organic molecule can lead to decomposition or oxidative side
reactions of ancillary functional groups in the molecule. We have
been exploring strategies to enable electrochemical oxidation
reactions to proceed at lower electrode potentials.[3] Use of an
electron-proton transfer mediator, such as an aminoxyl or
imidoxyl species, represents one appealing strategy, as these
mediators enable oxidations to proceed at electrode potentials >1
V lower than analogous non-mediated processes.[3b,c] In spite of
this progress, however, additional strategies are needed.
Hydrogen-atom transfer (HAT) mediators still require high
electrode potentials that constrain the functional group
compatibility,[3b,4] and we initiated the present study to explore
possible methods to address this challenge. Herein, we show that
use of iodide mediators in combination with visible-light
illumination provides the basis for sp3 C–H amination at low
electrode potentials.
-
an electrochemical mediator (Figure 1A, approach iv).[16] The I-/I3
/I2 redox couples are ~ 0.4 V lower than those for bromide[17] and
1–1.5 V lower than the electrode potentials required for the
electrochemical PCET and ET-PT-ET reactions (Figure 1B).
Our efforts were initiated by testing the three previously
reported electrochemical reaction conditions with two N-alkyl
A. Strategies for electrochemical HLF-type reactions
X
NR2
R
N-X
homolysis
R
H
R
H
R
H
R2
NHR2
NR2
[1,5]-HAT
N
R1
R1
R1
R1
X = I/Br
i
ii iii iv
- H+
h!
I-
+
R = Ar
Ar
+
Br-
NHR2
Base-promoted electrolysis
PCET
R1
+
Ar
Ar
NHR2
NHR2
ET
R = Ar
PT
- H+
ET
+
+
R1
R1
Selective formation of C(sp3)–N bonds via C–H/N–H coupling
is a transformation of longstanding interest.[ 5 ] The Hofmann–
Löffler–Freytag (HLF) reaction is a pioneering example of such
reactivity,[6,7] and numerous variations of the HLF reaction have
emerged for C–H halogenation and nitrogen-heterocycle
synthesis.[ 8 , 9 , 10 , 11 ] Electrochemical methods, summarized in
Figure 1, have been explored as a means to bypass the use of
undesirable stoichiometric oxidants or pre-generation of N–X
B. Anodic potentials
e- rich aromatics,
heteroaromatics, thioethers
Approximate oxidation
potential of different
functional groups
amides, alcohols,
ketones, aryl halides
I-
Br-
ET-PT-ET
PCET
+
0
1.0
Improved functional group tolerance
2.0
V vs Fc/Fc
[*]
Dr. F. Wang, Prof. S. S. Stahl
Department of Chemistry
University of Wisconsin-Madison
Madison, WI 53706 (USA)
E-mail: stahl@chem.wisc.edu
Figure 1. Electrochemical strategies for dehydrogenative amination of sp3 C–H
bonds (A) and the associated anodic potentials required for each approach (B).
ET = electron transfer, PT = proton transfer, PCET = proton-coupled electron
transfer.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201813960
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Table 1. Combined electrochemical/photochemical iodide-mediated process for
sulfonamide derivatives, 1a and 1b, which differ by the presence
of the electron-rich methoxynaphthyl substituent in 1b (Scheme
1). Good reactivity and product yields were observed with 1a
under each of the three reported conditions. In contrast, negligible
C–N bond formation was observed for 1b, and nearly complete
consumption of the starting material led to a complex mixture of
products in each case. With these benchmarks established, we
turned our attention to electrochemical conditions with iodide as a
mediator. Shono's original report on bromide-mediated C–H
amination included one example of iodide-mediated reactivity;[14]
however, the N-iodo intermediates tend to undergo beta-
elimination of HI to afford imine-derived products under thermal
conditions. This insight, together with the use of visible-light
promoted homolysis of the N–I bond in PhI(OAc)2/I2-promoted
HLF-type reactions, prompted us to consider iodide-mediated
electrochemical conditions illuminated by a compact fluorescent
light (CFL) bulb.
C–H amination.[a]
OMe
NHSO2Ph
Ph
TBAI (10 mol%), KPF6 (0.1 M)
CH3CN/TFE (17:1)
RT, graphite II Pt
CP @ xx V vs Fc/Fc+
PhO2SN
CFL (20 W)
1b, 0.1 M
2b
OMe
Ph
Potential/V vs Fc/Fc+
TBAI
Entry
Yield/%
1
0.3
0.4
0.5
0.5
0.5
4%
70%
10 mol%
10 mol%
10 mol%
-
2
3
75% (72%)
n.d.
4
5[b]
19%
10 mol%
[a] The reaction was performed on a 0.5 mmol scale under constant potential
(CP) conditions, yields were determined by 1H NMR with m-xylene as an internal
standard; isolated yield shown in parenthesis. [b] Without irradiation. TFE =
2,2,2-Trifluoroethanol. n.d. = not detected.
Ar
Ar
TsHN
TsN
Ph
PhO2SNH
Ph
PhO2SN
Ph
3a, bearing an electron-rich anisole substituent. Using the
conditions optimized for 1b, the desired product 4a was obtained
in 54% yield with 18% recovered starting material (Table 2, entry
1). A comparable yield was obtained at lower applied potential
(0.3 V vs Fc/Fc+, entry 2), while an improved result was obtained
at higher potential (0.7 V; entry 3).[20] Inclusion of 1 equivalent of
pyridine in the reaction mixture led to further improvement in the
yield (82%, entry 4; similar beneficial effects of pyridine were not
observed with 1a and 1b – see Supporting Information for details).
Control experiments again revealed that no product was observed
in the absence of mediator or in the dark (entries 5 and 6).
Ph
1a
2a
1b
2b
Electrochemical
Method
Yield (conversion)
2a
2b
ET-PT-ET[a]
PCET[b]
52% (84%)
n.d. (100%)
Ar =
86% (100%) < 10% (100%)
71% (85%) < 10% (100%)
OMe
[c]
Br-
Scheme 1. Comparison of previous electrochemical methods for sp3 C–H
amination. For detail procedures, see refs. 12–14 and Supporting Information.
Yields were determined by 1H NMR with m-xylene as internal standard,
conversion is shown in parenthesis. [a] Conditions: 1a or 1b (0.2 mmol) and
nBu4NPF6 (0.1 M) in HFIP (10 mL), 2.5 mA, RT. [b] Conditions: 1a or 1b (0.2
mmol), NaOAc (0.2 mmol) and nBu4NBF4 (0.2 mmol) in DCE/HFIP (6 mL, 2:1),
7.5 mA, RT. [c] 1a or 1b (0.4 mmol), NaOMe (0.2 mmol) and KBr (0.2 mmol) in
methanol (6 mL) at 65 °C, 100 mA, DCE = 1,2-dichloroethane. HFIP =
1,1,1,3,3,3-hexafluoro-2-propanol. n.d. = not detected.
Table 2. Combined electrochemical/photochemical iodide-mediated process for
dehydrogenative amination of imidate.[a]
CCl3
TBAI (10 mol%), KPF6 (0.1 M)
N
O
CCl3
NH
CH3CN/TFE (17:1)
RT, graphite II Pt
CP @ xx V vs Fc/Fc+
CFL (20 W)
O
MeO
MeO
Representative data with 1b are shown in Table 1. The
reactions were conducted in an undivided glass electrolysis cell
with CFL illumination, using 10% tetrabutylammonium iodide
(TBAI) as the mediator, 0.1 M KPF6 as supporting electrolyte, a
graphite rod anode, a Pt wire cathode, and TFE as a co-solvent
in CH3CN (see Supporting Information for details). An applied
potential of 0.3 V vs. Fc/Fc+, which is above the I-/I3- redox wave
3a, 0.1 M
4a
Potential/V vs Fc/Fc+
TBAI
Yield/%
Entry
1
0.5
0.3
0.7
0.7
0.7
0.7
54%
47%
71%
10 mol%
10 mol%
10 mol%
10 mol%
-
2
3
4[b]
5[b]
6[b,c]
82% (73%)
n.d.
-
and near the I3 /I2 mid-point potential (see Figure S1), led to only
2%
10 mol%
small amounts of product 2b (4%), with most of the starting
material recovered unreacted (81%) (entry 1). Improved yields
were observed at a higher applied potential, with a 75% yield
obtained at 0.5 V (Table 1, entry 2-3). No product was generated
in the absence of mediator, and much lower product yield (19%)
was observed in the dark (entries 4-5).
[a] The reaction was performed on a 0.5 mmol scale under constant potential
(CP) conditions, yields were determined by 1H NMR with m-xylene as an internal
standard; isolated yield shown in parenthesis. [b] With 1 equiv of pyridine. [c]
Without irradiation. TFE = 2,2,2-Trifluoroethanol. n.d. = not detected.
A number of different N-alkyl sulfonamide and imidate
substrates were then evaluated under the optimized iodine-
mediated photo/electrochemical conditions to assess their ability
to undergo dehydrogenative cyclization (Table 3). Table 3A
shows the results with N-alkyl sulfonamide derivatives, while
Table 3B illustrates the scope of imidates compatible with the
These promising results with a tosylamide substrate prompted
us to consider C–H/N–H coupling with a substrate bearing an
imidate nucleophile. HLF-type reactivity with this substrate class
was recently demonstrated by the groups of Nagib and Chen with
-
stoichiometric chemical oxidants (PhI(OAc)2/I3 and N-iodo-
succinimide/Ag2O, respectively),[ 18 , 19 ] but no electrochemical
precedent has been reported. The experiments were initiated with
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Table 3. Substrate scope of iodide-mediated dehydrogenative amination.[a,b]
A. Scope for pyrrolidine synthesis
OMe
SO2Ph
SMe
N
SO2Ph
R1
Ts
h!
TsN
Ph
N
N
NHTs
Ph
Ph
I-/I2
R
R1
Table 1, entry 3
+
R
1
2
2a, 71%[c]
2b, 72%[d]
2c, 65%[d]
OMe
Me
SO2Ph
N
SO2Ph
H
O
NTs
OMe
TsN
OMe
Me
PhO2S
N
Ph
Ph
TsN
N
C3H7
2g, 44%[e]
2d, 79%[d]
B. Scope for oxazoline synthesis
2e, 82%[d]
2h, 67%[d]
2i, 63%[f]
2f, 57%
CCl3
CCl3
O
R
N
N
CCl3
h!
O
3
CCl3
NH
O
4a, R = OMe, 73%
4b, R = F, 75%
4c, R = H, 85%
4d, R = Cl, 61%
R
N
I-/I2
+
O
Table 2, entry 4
4e,R = Me, 67%
4f,R = Cl, 75%
R
R
4
CCl3
CCl3
O
CCl3
4g, R = Me, 72%
4h, R = OMe, 76%
4i, R = F, 74%
CCl3
CCl3
O
N
N
N
N
N
O
O
O
R
4j, R = Cl, 67%
S
S
4k, R = CF3, 52%[g]
4l, 83%
4m, 69%
CCl3
4n, 61%
4o, 79%
CCl3
CCl3
CCl3
O
CCl3
O
CCl3
O
Ar
N
Cl
Cl
Cl
N
N
N
N
N
N
O
O
O
O
C3H7
PhS
MeO
Ar = 4-F-Phenyl
N
N
Cl
4r, 67%[g]
4s, 71%[g]
4p, 86%
4q, 75%
4t, 60%
4u, 65%
4v, 52%
C. 1,2-amino alcohols synthesis from imidate
O
O
O
O
R
HN
CCl3
OH
HN
CCl3
OH
h!
HN
CCl3
OH
5a, R = H, 66%
5b, R = OMe, 58%
5c, R = Cl, 67%
O
CCl3
NH
HN
CCl3
OH
F
TsOH
I-/I2
Ar
+
Ar
S
as above
5d, 54%
5e, 59%
3
5
[a] The reaction was conducted on a 0.5 mmol scale, see Supporting Information for details. [b] Isolated yield. [c] 2a has also been produced under conditions
-
with stoichiometric chemical oxidants: PhI(OAc)2/cat. I2, 90%;11a PhI(OAc)2/I3 , 93%;10g mCPBA/cat. I2, 54%;11c [d] dr = 1:1. [e] dr = 1.8:1. [f] dr = 1.2 :1. [g] With
2,6-lutidine instead of pyridine as additive. TsOH = p-toluenesulfonic acid.
reaction conditions. Substrates of both classes with electron-rich
arenes were effectively converted to the corresponding
pyrrolidine and oxazoline products under the optimized conditions
(2b-2e, 2i and 4a, 4h, 4n, 4o, 4t, respectively). The oxazoline
products derived from the imidate cyclization are appealing
precursors to 1,2-aminoalcohol derivatives (Table 3C).[18a,19]
The majority of products arise from functionalization of
activated C–H bonds (e.g., benzylic or adjacent to a heteroatom),
but successful reactivity was also observed with unactivated
aliphatic C–H bonds (2g, 2h, 2i, 4v). The generation of 2h reveals
the expected preference of secondary over primary C–H
functionalization.[10f] Effective substrates feature an array of
aromatic substituents, including electron-rich and electron-
deficient substituted arenes, in addition to thiophene and pyridine.
The good functional group tolerance enabled by merging
(benzo)thiophene, benzofuran, benzothiazole, pyridine, and
carbamate derivatives, while partial decomposition and lower
yields of 2a were observed with indole, furan and aniline
derivatives.
The observed reactivity is readily rationalized by an
electrochemical circuit consisting of generation of I2 at the anode
and hydrogen evolution at the cathode (Scheme 2A). The latter
reaction contributes to the overall catalytic process by generating
a Brønsted base that promotes iodination of the N–H substrate,
which then initiates the non-electrochemical C–H functionalization
sequence that takes place in bulk solution (Scheme 2B).[ 22 ]
Photolysis contributes to homolysis of the N–I bond and enables
formation of the N-centered radical that undergoes 1,5-hydrogen
atom transfer (HAT) to generate an alkyl radical. Subsequent
trapping of the radical with iodine generates an alkyliodide
intermediate that can undergo Brønsted base-promoted
nucleophilic displacement by the appended nitrogen nucleophile.
photochemistry with
a low-potential mediator was further
demonstrated with an intermolecular additive screening
experiment for the reaction of 1a (see Table S5 in the Supporting
Information for details).[ 21 ] Functional groups shown to be
compatible with the reaction conditions include carbazole,
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A. Reactions at the electrode
350
250
150
50
B: = CF3CH2O-
1a
2 I-
H
2 B: +
2
3a
bulk solution
processes
(see below)
Anode
Cathode
-
1c
I2
2 BH+
1b
-
I-
I3
I2
3t
B. Bulk solution processes
H
I
•
NTs
NTs h!
1/2 I2
NTs
Ph
Ph
BH+ + I-
Ph
B: + I2
-50
1,5-HAT
-0.5
0
0.5
1
1.5
2
2.5
E(V) vs. Fc/Fc+
I
BH+ + I- B:
TsN
•
1/2 I2
NHTs
NHTs
Ph
Ph
Ph
Scheme 3. CVs of iodide and representative substrates. Conditions: 5 mM
substate in acetonitrile with KPF6 (0.1 M) as supporting electrolyte, glassy
carbon as working electrode (~ 7.0 mm2) and a platinum wire counter electrode,
scan rate = 100 mV/s.
Scheme 2. Simplified mechanism for photo/electrochemical iodide-mediated
dehydrogenative C–H/N–H coupling.
Overall, the results outlined herein demonstrate a novel
photochemical/electrochemical strategy to enable C–H amination
reactions to be conducted at lower applied potentials. In addition
to the above comparisons with ET-PT-ET and PCET-based
reactions, the results may be compared to other electrochemical
C–H oxidation reactions that proceed via HAT mechanisms.
Phthalimido-N-oxyl (PINO) is perhaps the most widely used HAT
reagent in electrochemical C–H oxidation reactions.[2k,3b,4a-d] The
Functional group tolerance is achieved by the combined use
of a low-potential mediator (I-/I2) with photochemical activation of
the N-iodo intermediate generated under the reaction
conditions.[23] The anodic potential needed to (re)generate I2 at
the anode (0.3–0.7 V vs. Fc/Fc+) is well below the redox potential
of electron-rich arenes and other substituents. This feature is
illustrated in Scheme 3, which shows cyclic voltammograms (CVs)
of the iodide mediator, including both the I-/I3 and I3 /I2 redox
couples, and several representative substrates. Comparison of
the CVs for 1a and the substrates with electron-rich aromatic
substituents highlights the functional-group compatibility
challenges that will be encountered in reactions initiated by direct
electrochemical oxidation of substrate or proton-coupled
oxidation of the nitrogen nucleophile (cf. ET-PT-ET and PCET
processes in Scheme 1). The ET and PCET steps associated with
these reactions often require applied potentials well above that of
many valuable functional groups and will initiate substrate
decomposition or undesirable side reactions. For example, ET
from the arene ring in 1a exhibits a peak potential of 1.9 V
(Scheme 3), and the PCET-initiated reactions proceed with
anodic potentials of >2 V.[24,25] While the ET-PT-ET and PCET
processes will have utility for substrates that tolerate high anode
potentials, the magnitude of the applied potential will intrinsically
limit the scope.
-
-
–
I3 /I2 redox potential is ~0.2–0.6 V lower than the potentials
needed to generate PINO from N-hydroxyphthalimide (NHPI).[26]
This difference is amplifed when one considers that the N-
centered radicals generated in the present reactions are much
stronger H-atom acceptors than PINO (estimated BDEs:
NHPI(O–H) ~ 88 kcal/mol, sulfonamide and imidate (N–H) > 100
kcal/mol[ 27 ]). Thus, the combination of electrochemical and
photochemical energy inputs allows more potent oxidants to be
generated at lower electrode potentials, thereby enabling the C–
H/N–H dehydrogenative coupling reaction to proceed with broad
functional group tolerance. We anticipate that many other
electrochemical redox processes will benefit from application of
principles similar to those described here.
Acknowledgments
Financial support was provided from an SIOC fellowship (F.W.),
and the NIH (R01 GM100143 for S.S.S.). Spectroscopic
instrumentation was supported by a gift from Paul. J. Bender, the
NSF (CHE- 1048642), and the NIH (1S10 OD020022-1).
Conflict of interest:
The authors declare no conflict of interest.
Keywords: C-H Functionalization, Amination, Iodine, Electrolysis,
Photochemistry.
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[1]
a) S. Torii, Novel Trends in Elecroorganic Synthesis, Springer-Verlag,
Tokyo, 1998; b) H. Lund, O. Hammerich, Organic Electrochemistry, 5th
ed., CRC Press, Boca Raton, 2015.
[10] For PhI(OAc)2/I2 oxidation systems, see: a) P. De Armas, R. Carrau, J. I.
Concepción, C. G. Francisco, R. Hernández, E. Suárez, Tetrahedron Lett.
1985, 26, 2493; b) R. L. Dorta, C. G. Francisco, E. Suárez, J. Chem. Soc.,
Chem. Commun. 1989, 1168; c) M. Katohgi, H. Togo, K. Yamaguchi, Y.
Masataka, Tetrahedron 1999, 55, 14885; d) C. G. Francisco, A. J.
Herrera, E. Suárez, J. Org. Chem. 2003, 68, 1012; e) R. Fan, D. Pu, F.
Wen, J. Wu, J. Org. Chem. 2007, 72, 8994; f) N. R. Paz, D. Rodríguez-
Sosa, H. Valdés, R. Marticorena, D. Melián, M. B. Copano, C. C.
González, A. J. Herrera, Org. Lett. 2015, 17, 2370; g) E. A. Wappes, S.
C. Fosu, T. C. Chopko, D. A. Nagib, Angew. Chem. Int. Ed. 2016, 55,
9974. h) J. L. Courtneidge, J. Lusztyk, D. Pagé, Tetrahedron Lett. 1994,
35, 1003.
[2]
For representative recent reviews, see: a) J. B. Sperry, D. L. Wright,
Chem. Soc. Rev. 2006, 35, 605; b) J.-i. Yoshida, K. Kataoka, R.
Horcajada, A. Nagaki, Chem. Rev. 2008, 108, 2265; c) R. Francke,
Beilstein J. Org. Chem. 2014, 10, 2858; d) M. Yan, Y. Kawamata, P. S.
Baran, Chem. Rev. 2017, 117, 13230; e) Y. Jiang, K. Xu, C. Zeng, Chem.
Rev. 2018, 118, 4485; f) D. Pletcher, R. A. Green, R. C. D. Brown, Chem.
Rev. 2018, 118, 4573; g) S. Tang, Y. Liu, A. Lei, Chem 2018, 4, 27; h) A.
Wiebe, T. Gieshoff, S. Möhle, E. Rodrigo, M. Zirbes, S. R. Waldvogel,
Angew. Chem. Int. Ed. 2018, 57, 5594; i) S. Möhle, M. Zirbes, E. Rodrigo,
T. Gieshoff, A. Wiebe, S. R. Waldvogel, Angew. Chem. Int. Ed. 2018, 57,
6018; j) Q.-L. Yang, P. Fang, T.-S. Mei, Chin. J. Chem. 2018, 36, 338; k)
J. E. Nutting, M. R. Rafiee, S. S. Stahl, Chem. Rev. 2018, 118, 4834.
For examples, see: a) A. Badalyan, S. S. Stahl, Nature 2016, 535, 406;
b) M. Rafiee, F. Wang, D. P. Hruszkewycz, S. S. Stahl, J. Am. Chem.
Soc. 2018, 140, 22; c) F. Wang, M. Rafiee, S. S. Stahl, Angew. Chem.
Int. Ed. 2018, 57, 6686; d) A. J. Lennox, S. L. Goes, M. P. Webster, H.
F. Koolman, S. W. Djuric, S. S. Stahl, J. Am. Chem. Soc. 2018, 140,
11227.
[11] For examples of I2-catalyzed HLF reactions with various oxidants, see:
a) C. Martínez, K. Muñiz, Angew. Chem. Int. Ed. 2015, 54, 8287; b) P.
Becker, T. Duhamel, C. J. Stein, M. Reiher, K. Muñiz, Angew. Chem. Int.
Ed. 2017, 56, 8004; c) T. Duhamel, C. J. Stein, C. Martínez, M. Reiher,
K. Muñiz, ACS Catal. 2018, 8, 3918; d) L. M. Stateman, E. A. Wappes,
K. M. Nakafuku, K. M. Edwardsand, D. A. Nagib, Chem. Sci. 2019, DOI:
10.1039/c8sc05685d.
[3]
[4]
[12] S. Herold, D. Bafaluy, K. Muñiz, Green Chem., 2018, 20, 3191.
[13] X. Hu, G. Zhang, F. Bu, L. Nie, A. Lei, ACS Catal. 2018, 8, 9370.
[14] T. Shono, Y. Matsumura, S. Katoh, K. Takeuchi, K. Sasaki, T. Kamada,
R. Shimizu, J. Am. Chem. Soc. 1990, 112, 2368.
a) M. Masui, S. Hara, T. Ueshima, T. Kawaguchi, S. Ozaki, Chem. Pharm.
Bull. 1983, 31, 4209; b) M. Masui, T. Kawaguchi, S. Ozaki, S. J. Chem.
Soc., Chem. Commun. 1985, 1484; c) E. J. Horn, B. R. Rosen, Y. Chen,
J. Tang, K. Chen, M. D. Eastgate, P. S. Baran, Nature 2016, 533, 77; d)
D. P. Hruszkewycz, K. C. Miles, O. R. Thiel, S. S. Stahl, Chem. Sci. 2017,
8, 1282; e) Y. Kawamata, M. Yan, Z. Liu, D.-H. Bao, J. Chen, J. T. Starr,
P. S. Baran, J. Am. Chem. Soc. 2017, 139, 7448.
[15] See also: S. Zhang, L. Li, M. Xue, R. Zhang, K. Xu, C. Zeng, Org. Lett.
2018, 20, 3443.
[16] For recent review on iodide-mediated electrolysis, see: K. Liu, C. Song,
A. Lei, Org. Biomol. Chem. 2018, 16, 2375. For representative examples,
see: b) W.-J. Gao, W.-C. Li, C.-C. Zeng, H.-Y. Tian, L.-M. Hu, R. D. Little,
J. Org. Chem. 2014, 79, 9613; c) J. Chen, W.-Q. Yan, C. M. Lam, C.-C.
Zeng, L.-M. Hu, R. D. Little, Org. Lett. 2015, 17, 986; d) S. Liang, C.-C.
Zeng, H.-Y. Tian, B.-G. Sun, X.-G. Luo, F.-Z. Ren, J. Org. Chem. 2016,
81, 11565; e) Q.-Q. Wang, K. Xu, Y.-Y. Jiang, Y.-G. Liu, B.-G. Sun, C.-
C. Zeng, Org. Lett. 2017, 19, 5517; f) S. Tang, X. Gao, A. Lei, Chem.
Commun. 2017, 53, 3354; g) H. Wang, J. Zhang, J. Tan, L. Xin, Y. Li, S.
Zhang, K. Xu, Org. Lett. 2018, 20, 2505.
[5]
a) Amino Group Chemistry: From Synthesis to the Life Sciences (Eds.:
A. Ricci), Wiley-VCH, Weinheim, 2008, pp. 55-92; b) H. M. L. Davies, J.
R. Manning, Nature 2008, 451, 417; c) T. Newhouse, P. S. Baran, Angew.
Chem. Int. Ed. 2011, 50, 3362; d) Y. Park, Y. Kim, S. Chang, Chem. Rev.
2017, 117, 9247.
[6]
[7]
For reviews, see: a) M. E. Wolff, Chem. Rev. 1963, 63, 55; b) Name
Reactions in Heterocyclic Chemistry (Eds.: J.-J. Li, E. J. Corey), Wiley,
Hoboken, 2005; c) L. M. Stateman, K. M. Nakafuku, D. A. Nagib,
Synthesis 2018, 50, 1569.
[17] For CV studies of TBAI and TEABr in CH3CN with KPF6 as supporting
electrolyte, see Supporting Information.
For early examples, see: a) A. W. Hofmann, Ber. Dtsch. Chem. Ges.
1879, 12, 984; b) A. W. Hofmann, Ber. Dtsch. Chem. Ges. 1883, 16, 558;
c) K. Löffler, C. Freytag, Ber. Dtsch. Chem. Ges. 1909, 42, 3427; d) E. J.
Corey, W. R. Hertler, J. Am. Chem. Soc. 1960, 82, 1657; e) S. W.
Baldwin, R. J. Doll, Tetrahedron Lett. 1979, 20, 3275.
[18] See the following and ref. 11d; E. A. Wappes, K. M. Nakafuku, D. A.
Nagib, J. Am. Chem. Soc. 2017, 139, 10204.
[19] X.-Q. Mou, X.-Y. Chen, G. Chen, G. He, Chem. Commun. 2018, 54, 515.
[20] Although it is unclear at this stage, the higher applied potential needed
to get excellent yield possibly stems from the deactivation of electrode
[8]
For recent examples with pre-formed N-X species as substrates, see: a)
H. Togo, Y. Hoshina, T. Muraki, H. Nakayama, M. Yokoyama, J. Org.
Chem. 1998, 63, 5193; b) L. R. Reddy, B. V. S. Reddy, E. J. Corey, Org.
Lett. 2006, 8, 2819; c) K. Chen, J. M. Richter, P. S. Baran, J. Am. Chem.
Soc. 2008, 130, 7247; d) K. Chen, P. S. Baran, Nature 2009, 459, 824;
e) E. C. Cherney, J. M. Lopchuk, J. C. Green, P. S. Baran, J. Am. Chem.
Soc. 2014, 136, 12592; f) Q. Qin, S. Yu, Org. Lett. 2015, 17, 1894; g) B.
J. Groendyke, D. I. Abusalim, S. P. Cook, J. Am. Chem. Soc. 2016, 138,
12771; h) M. A. Short, J. M. Blackburn, J. L. Roizen, Angew. Chem. Int.
Ed. 2018, 57, 296.
during bulk electrolysis.
[21] K. D. Collins, F. Glorius, Acc. Chem. Res. 2015, 48, 619.
[22] See Supporting Information for control experiments with stoichiometric
iodine as oxidant in the presence of different bases.
[23] See the Supporting Information for additive screening experiments under
the present iodide-mediated photo/electrochemical conditions.
[24] The PCET-initiated reactions in ref. 13 were conducted under constant
current conditions. The >2 V value noted here was determined by
monitoring the anode potential while reproducing the reported conditions.
[25] See Supporting Information for CV studies of TsNHMe with different
bases.
[26] NHPI oxidation takes place at ~0.5–0.9 V vs. Fc/Fc+, depending on the
identity of the proton acceptor. The potential is lower with stronger bases,
but PINO also decomposes more rapidly under basic conditions. See refs.
2k and 3b for further discussion.
[9]
For selected examples with N-H substrates, see: a) A. Verma, S. Patel,
Meenakshi, A. Kumar, A. Yadav, S. Kumar, S. Jana, S. Sharma, C. D.
Prasad, S. Kumar, Chem. Commun. 2015, 51, 1371; b) C. Q. O’Broin, P.
Fernández, C. Martínez, K. Muñiz, Org. Lett. 2016, 18, 436; c) J. Long,
X. Cao, L. Zhu, R. Qiu, C.-T. Au, S.-F. Yin, T. Iwasaki, N. Kambe, Org.
Lett. 2017, 19, 2793; d) T. Liu, M. C. Myers, J.-Q. Yu, Angew. Chem. Int.
Ed. 2017, 56, 306; e) S. Sathyamoorthi, S. Banerjee, J. Du Bois, N. Z.
Burns, R. N. Zare, Chem. Sci. 2018, 9, 100; f) P. Becker, T. Duhamel, C.
Martínez, K. Muñiz, Angew. Chem. Int. Ed. 2018, 57, 5166.
[27] a) Y.-R. Luo, Handbook of Bond Dissociation Energies in Organic
Compounds, CRC, Boca Raton, FL, 2002; b) D. Šakić, H. Zipse, Adv.
Synth. Catal. 2016, 358, 3983.
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10.1002/anie.201813960
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Synergistic benefits: Visible-light
irradiation is combined with an
electrochemical reaction that uses
iodine as a redox mediator to enable
efficient intramolecular C–H
Fei Wang, Shannon S. Stahl*
Page No. – Page No.
Merging Photochemistry with
Electrochemistry: Functional Group
Tolerant Electrochemical Amination
of sp3 C–H Bonds
Electron Rich
Functional
Groups
Typical
Substrate
amination. The combined
photo/electrochemical approach
allows the reactions to proceed with
low anode potentials, which tolerate a
wide range of functional groups.
Iodide as
mediator
-
I-
I3
I2
-0.5
0
0.5
1
1.5
2
2.5
E(V) vs. Fc/Fc+
This article is protected by copyright. All rights reserved.