Visible-Light Photocatalytic Double C-H Functionalization of Indoles: A Synergistic Experimental and Computational Study

Article abstract of DOI:10.1055/s-0036-1588719

Herein is disclosed a novel visible-light photocatalytic double C-H functionalization of indoles. The reaction affords 2,3-difunctionalized indoles in up to 84% yield, but the reaction rate depends strongly on electronic substituent effects. Mechanistic DFT studies and control experiments suggest that the secondary functionalization occurs through an independent photocatalytic oxidation of bromide ions formed during the reaction to generate molecular bromine capable of electrophilic C-3 bromination.

Full text of DOI:10.1055/s-0036-1588719

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Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
A
letter
Synlett
U. Erdenebileg et al.
Letter
Visible-Light Photocatalytic Double C–H Functionalization of
Indoles: A Synergistic Experimental and Computational Study
Uranbaatar Erdenebilega
Taye B. Demissieb
Jørn H. Hansen*a
a
Department of Chemistry, UiT The Arctic University of Norway,
Hansine Hansens veg 54, 9037 Tromsø, Norway
jorn.h.hansen@uit.no
Centre for Theoretical and Computational Chemistry (CTCC),
b
Department of Chemistry, UiT The Arctic University of Norway,
9037 Tromsø, Norway
Received: 14.11.2016
Accepted after revision: 26.01.2017
Published online: 21.02.2017
DOI: 10.1055/s-0036-1588719; Art ID: st-2016-d0763-l
Abstract Herein is disclosed a novel visible-light photocatalytic double
C–H functionalization of indoles. The reaction affords 2,3-difunctional-
ized indoles in up to 84% yield, but the reaction rate depends strongly
on electronic substituent effects. Mechanistic DFT studies and control
experiments suggest that the secondary functionalization occurs
through an independent photocatalytic oxidation of bromide ions
formed during the reaction to generate molecular bromine capable of
electrophilic C-3 bromination.
Key words photocatalysis, C–H functionalization, indoles, DFT, reac-
tion mechanism
C–H functionalization of heterocycles has become a ma-
Jørn H. Hansen received his PhD in organic chemistry from Emory Uni-
versity (Atlanta, GA) in 2010, followed by postdoctoral research at
Princeton University, before joining UiT The Arctic University of Norway
as an Associate Professor of Chemistry in 2012. His research interests
range from development and applications of novel late-stage function-
alization methods, chemical library design with bioactive and functional
heterocycles, via computational mechanistic analysis to chemical edu-
cation.
1–4
jor area of research in chemical synthesis. The prevalence
of heterocycles in medicinal and biologically relevant mole-
cules underscores the need for novel chemical methods to
5–11
achieve complex and efficient transformations.
Late-
stage functionalization is becoming a leading strategy for
5
efficient introduction of specific functional groups, or to
generate chemical libraries, for complex bioactive mole-
5,7,10,12,13
cules.
Visible-light photocatalysis (VLPC) has recently
emerged as a powerful manifold for late-stage C–H func-
One of the first examples of selective intermolecular C–
H functionalization of heterocycles using VLPC came from
Stephenson and co-workers, who showed that indoles and
1–4,7,8,14
7
tionalization.
An excellent example is the recent pro-
6
tocol reported by DiRocco and co-workers, exemplified by
the selective methylation of the antifungal agent
voriconazole (Scheme 1), which was achieved in overall 75%
yield to produce a mixture of mono- and dimethylated
products via iridium photocatalysis. Considering the num-
ber of C–H sites available for functionalization, and the
presence of other potentially interfering functional groups,
this is an impressive achievement. These results truly un-
derscore the potential for design of late-stage functionaliza-
tion strategies using VLPC.
other heteroaromatics readily underwent C–H malonation
under photocatalytic conditions with diethyl bromom-
alonate and using 4-methoxy-N,N-diphenylaniline as base.
For example, the C-2 malonation of N-methylindole was
achieved in 82% yield using 1 mol% of ruthenium(II) trisbi-
7
pyridine dichloride as the photocatalyst (Scheme 1). In this
letter, we describe our recent discovery of a photocatalytic
double C–H functionalization process using indoles and di-
ethyl bromomalonate. Our experimental efforts to under-
stand the mechanism and scope, and to advance further de-
velopment of this process, are detailed herein. Moreover,
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U. Erdenebileg et al.
Letter
DiRocco et al. 2014
observed after 48 hours reaction time, consistent with Fig-
ure 1. As shown in Scheme 2 and Figure 1, 1 and 2 are pro-
duced via the main reaction path a.
O
F
O
Me
F
Me
N
O
Me
HO
Me
HO
N
N
N
N
N
N
N
F
hν
Ir(III)
N
F
N
Me
F
F
7
5%
voriconazole
anti fungal agent)
mono/di
2.9:1
(
Stephenson et al. 2010
Br
CO2Et
CO2Et
Ru(bpy)3Cl2 (1 mol%)
CO2Et
2
N
N
CO Et
blue LED (1 W, 435 nm)
4-MeOC H NPh
Me
Me
6
4
2
DMF, rt, 12 h
82%
Scheme 1 Photocatalytic C–H functionalization of biologically inter-
esting heterocycles
we have synergistically employed density functional theory
calculations to assess a likely mechanism for the transfor-
mation.
Figure 1 Product distribution as function of time for model reaction
Our work commenced with surveying reactions avail-
able in the literature. We attempted to reproduce the result
by Stephenson and co-workers in which they achieved C-2
On the other hand, reaction path b is operating, al-
though slow compared to a, and yields C3-malonated prod-
uct 3, which is a precursor for the formation of 4. Figure 1
shows that 1 and 3 are formed in parallel, but that the for-
mation of 1 is much faster. Moreover, the conversion study
demonstrates that formation of 4 comes exclusively from 3.
Finally, we have confirmed that 1 and 3 convert exclusively
into 2 and 4, respectively, by control experiments in which
pure 1 and 3 were separately subjected to the reaction con-
ditions.
7
malonation of N-methylindole (Scheme 1). We obtained a
somewhat lower yield of 68% after 12 hours, but observed
that the chemical yield appeared to decrease over time. Af-
ter 48 hours reaction time, a new species was observed as
the major product and identified as the 2,3-difunctional-
ized indole 2, in which the C-2 position contained the malo-
nyl group, and the C-3 position was functionalized with
bromine (Scheme 2). An ultra-high performance liquid
chromatography (UPLC) study of the reaction progress re-
vealed that product 1 is formed initially with a peaking con-
centration after ca. 10 hours (Figure 1). The difunctional-
ized indole 2 steadily grows in, reaching the maximum
yield region after ca 24 hours. An 84% isolated yield of 2 was
The influence of reaction conditions was surveyed to
identify parameters of importance to control the product
distribution in favor of compound 2 (Table 1). The reaction
works with different common photocatalysts, although ru-
thenium(II) trisbipyridine hexahydrate afforded the largest
amount of 2 after 48 hours reaction time. The reaction also
worked in different solvents such as dichloromethane and
acetonitrile, but the highest yield of 2 was observed in DMF.
The base is a crucial factor, and only the triaryl base 4-
MeOC H NPh was effective at affording high yields of the
Br
COOEt
COOEt
COOEt
COOEt
6
4
2
N
N
desired product. The reactions are conducted using two
equivalents of diethyl bromomalonate, which afforded a
satisfactory reaction rate according to Figure 1. However,
when one equivalent of diethyl bromomalonate was em-
ployed, much slower conversion was observed, but product
Me
1 (0%)
Me
2 (84%)
COOEt
(2 equiv)
COOEt
Ru(bpy)3Cl2·6H2O (1 mol%)
Br
Path a
Path b
N
4
-MeOC6H4NPh2 (2 equiv)
2
was still formed as the major product after ca. 4–5 days.
Me
DMF, Ar
This result strongly suggests that both the bromine and the
malonyl group in the final product come from the same
equivalent of substrate. For a general procedure and repre-
sentative analytical data, see reference 15.15
To investigate the generality of the newly discovered
double C–H functionalization process, various substrates
were studied under the best reaction conditions from Table
EtOOC
blue LEDs EtOOC
COOEt
COOEt
COOEt
N
COOEt
N
Me
Me
(4%)
3
4 (5%)
Scheme 2 Observed products in the model reaction
1. Table 2 shows the isolated yields of C-2 malonated het-
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U. Erdenebileg et al.
Letter
Table 1 Influence of Reaction Variablesa
Entry
Catalyst
Base
Solvent
Yield (%)b
1
2
3
4
1
Ru(bpy)
3
(PF
6
)
2
4-MeOC
6
6
6
6
6
6
6
6
H
H
H
H
H
H
H
H
4
4
4
4
4
4
4
4
NPh
NPh
NPh
NPh
NPh
NPh
NPh
NPh
2
2
2
2
2
2
2
2
DMF
DMF
DMF
4
6
81
78
77
84
7
7
6
7
6
1
4
4d
5
3
0
0
1
8
10
11
8
2
fac-Ir(ppy)
3
4-MeOC
4-MeOC
4-MeOC
4-MeOC
4-MeOC
4-MeOC
4-MeOC
3
Ir(ppy) (dtbbpy)PF
2
6
5
4
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
3
3
3
3
3
3
3
3
3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
2
·6H
·6H
·6H
·6H
·6H
·6H
·6H
·6H
·6H
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
CH
2
Cl
2
2
5c
6
toluene
MeCN
DMF
19
11
0
3
74
84d
26
2
11
5d
5
7
8c,e
9c
DMF
57
1
Et
3
N
DMF
2
1
0c
1c
2c
DIPEA
pyridine
DBU
DMF
0
0
0
1
DMF
0
0
0
1
a
DMF
0
0
3
Unless otherwise stated, the reaction conditions were: N-methylindole (0.5 mmol), diethyl bromomalonate (1.0 mmol, 2.0 equiv), photocatalyst (0.005 mmol,
1
.0 mol%), base (1.0 mmol, 2.0 equiv), and solvent (2 mL), argon atmosphere, 1 W blue LED light (for ruthenium-based catalysts) or 1 W white LED strips (for
iridium-based catalysts) at r.t., 48 h.
b
Unless otherwise stated, yields were calculated on the basis of UPLC analysis of the crude products.
c
N-Methylindole was not fully consumed after 48 h.
d
Isolated yields.
With only 1 equiv of diethyl bromomalonate.
e
Table 2 Isolated Yields of Mono- and Disubstituted Derivatives from Indoles, Benzofuran and Benzothiophene after 48 Hours of Reactiona
COOEt
R
R
Br
Br
R
COOEt
+
COOEt
COOEt
COOEt
COOEt
X
X
X
Ru(bpy)3Cl2·6H2O
4
-MeOC6H4NPh2
blue LEDs
5
6
7
Entry
Substrate
Product
Yield (%)
Product
Yield (%)
1
2
3
4
5
6
7
8
9
5a X = NH; R = H
6a
6b
6c
6d
6e
6f
20
38
17
14
0
7a
7b
7c
7d
7e
7f
63
27
58
52
0
5b X = NH; R = 4-Br
5c X = NH; R = 5-Br
5d X = NH; R = 7-Br
5e X = NH; R = 5-MeO
5f X = NH; R = 5-NC
22
0
17
0
5g X = NH; R = 5-O
2
N
6g
6h
6i
7g
7h
7ab
7j
5h X = N(CH CO Me; R = H
2
)
3
2
27
82
86
31
60
11
0
5i X = N-Boc; R = H
5j X = O, R = H
1
0
1
2
6j
1
5k X = S, R = H
6k
7k
0
1
6- and 7-azaindoles
no reaction observed
a
Reaction conditions: heterocyclic substrate (0.5 mmol), diethyl bromomalonate (1.0 mmol, 2.0 equiv), tris(bipyridine)ruthenium(II) chloride hexahydrate (0.005
mmol, 1.0 mol %), 4-methoxy-N,N-diphenylaniline (1.0 mmol, 2.0 equiv), and DMF (2 mL), argon atmosphere, 1 W blue LED strips at r.t., 48 h.
b
The Boc group was lost spontaneously during the reaction.
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U. Erdenebileg et al.
Letter
erocycles 6a–k and doubly functionalized products 7a–k.
For most substrates, full conversion to difunctionalized
product was not observed after 48 hours reaction time.
The reaction rates appeared very sensitive to the sub-
stituents, and in several cases, byproducts were also
formed from other pathways (Figure 2). As such, reaction
time is a crucial and very substrate-specific parameter. Un-
substituted indole (5a) afforded 7a in 63% yield, with 20% of
(17%), in addition to C-3 malonation (8% of 15); with the
major product being C-3 brominated product 16 formed in
32% yield. 5-Nitroindole (5g) did not yield any desired
product, but afforded C-3 brominated indole 17 in 45%
yield (Figure 2). These interesting observations suggest that
the bromination can occur independently from the malona-
tion and that electron-poor substrates favor the former over
the latter process. The N-substituted indole 5h afforded
60% of 7h, suggesting that inductive electron-withdrawing
effects of N-substituents also cause reduced conversion
rates to the desired difunctionalized product. In this case,
the C-3 malonated product 18, arising from path b, was also
observed in 6% yield. Boc-protected indole 5i afforded 11%
of deprotected product 7a, consistent with the above-men-
tioned electronic effects. The deprotection occurs sponta-
neously under the reaction conditions. Attempts to extend
the chemistry to benzofuran (5j), benzothiophene (5k) and
azaindoles failed to produce any difunctionalization. In the
cases of 5j and 5k the C-2 monofunctionalized products
were observed exclusively in 86% and 31% yields, respec-
tively. No conversion was observed for the azaindoles.
We next attempted to extend the difunctionalization
chemistry to more basic heterocycles such as pyrrole (19a),
furan (19b), and thiophene (19c) (Table 3). In these cases,
we did not observe any bromination, only mixtures of mo-
no- (20a–c) and dimalonated (21a–c) products.
6a, indicating that slightly less electron-rich indoles require
longer reaction times to be converted fully into the desired
product. In a series of brominated indoles 5b–d, the difunc-
tionalized product 7b was minor in the case of 4-bromoin-
dole (27% 7b vs. 38% of 6b). Moreover, the formation of the
C3 homodimer 8 (Figure 2) was observed in 18% yield. In
this case, the combined substituent effects of the 4-bromo
and 2-malonyl groups must have rendered 6b amenable to
photooxidation and subsequent homodimerization. In 5-
and 7-substituted indoles the yields of difunctionalized
products were similar (58% and 52%, respectively). 5-Bromo
substitution appeared to more favor path b, as the products
9
and 10 were isolated in overall 21% yield (Figure 2). 7-Bro-
moindole (5d) also afforded a small amount of dimalonated
product 11 in 18% yield, consistent with increased π-nucle-
ophilicity at C-4 in this system. The π-electron-donating
methoxy substituent in the 5-position did not afford any
desired product, but rather underwent dimalonation as
well as homodimerizations to give a range of products 12–
In order to understand our newly discovered double C–
H functionalization process, and to obtain mechanistic in-
formation to develop the chemistry further, we studied var-
ious mechanistic possibilities using contemporary DFT
14 (Figure 2). Too electron-rich π-systems lead to reaction
pathways involving oxidation of the indole with subsequent
side reactions over the bromination. 5-Cyanoindole (5f)
gave approximately equimolar amounts of 6f (22%) and 7f
COOEt
H
N
EtOOC
COOEt
EtOOC
EtOOC
EtOOC
COOEt
COOEt
COOEt
Br
COOEt
COOEt
Br
Br
Br
COOEt
N
H
N
H
N
N
COOEt
H
H
Br
COOEt
8, 18%
9, 9%
10, 12%
11, 18%
EtOOC
EtOOC
MeO
COOEt
NH
NH
COOEt
COOEt
COOEt
COOEt
MeO
MeO
EtOOC
MeO
COOEt
COOEt
MeO
COOEt
COOEt
COOEt
COOEt
N
H
N
N
H
H
12, 45%
13, 10%
14, 28%
EtOOC
COOEt
EtOOC
COOEt
Br
Br
NC
NC
O2N
N
N
N
H
N
H
H
MeOOC
18, 6%
15, 8%
16, 32%
17, 45%
Figure 2 Characterized byproducts and their isolated yields
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U. Erdenebileg et al.
Letter
techniques in conjunction with experimental control ex-
periments. A major goal was to try to understand how the
C–H bromination occurs.
The C-2 addition is the kinetically favored pathway with an
energy barrier of 8.9 kcal/mol in the addition step, com-
pared to 10.2 kcal/mol barrier for C-3 addition, consistent
with the observed product distribution in Figure 1.
Table 3 Isolated Yields of Mono- and Dimalonated Derivatives from
Pyrrole, Furan, and Thiophene
The computed and experimental product distributions
are in good agreement in this case and provide the ratio-
nale for our choice of computational methodology (see the
Supporting Information for comparison with alternative
method). The addition step is followed by exergonic single-
electron transfer (SET, –17.2 kcal/mol) and subsequent
elimination of bromide ion (–9.5 kcal/mol) to form 1. For
the bromination we assessed different possibilities (see the
Supporting Information for details). Inspired by recent
work by Meyer and co-workers,18 we hypothesized that the
reaction could involve electrophilic bromination by small
a
COOEt
Br
EtOOC
EtOOC
COOEt
COOEt
COOEt
COOEt
+
X
X
Ru(bpy)3Cl2·6H2O
X
COOEt
20
4-MeOC6H4NPh2
19
blue LEDs
21
Entry
Substrate
Product
Yield (%)
Product
Yield (%)
1
2
19a, X = NH
19b, X = O
19c, X = S
20a
20b
20c
51
20
54
21a
21b
21c
33
72
19
amounts of Br , formed via photocatalytic oxidation of bro-
2
3
mide ions that are generated throughout the reaction. Ex-
amples of mild bromination of C-2-substituted indoles in
DMF exist in the literature,19 and this was also found to be
feasible both computationally and by a control experiment.
a
Reaction conditions: heterocyclic substrate (0.5 mmol), diethyl bromom-
alonate (1.0 mmol, 2.0 equiv), tris(bipyridine)ruthenium(II) chloride hexa-
hydrate (0.005 mmol, 1.0 mol%), 4-methoxy-N,N-diphenylaniline (1.0
mmol, 2.0 equiv), and DMF (2 mL), argon atmosphere, 1 W blue LED strips
at r.t., 48 h.
In the control experiment, 1 was treated with Br in DMF
2
and was shown to convert fully into 2. Finally, the HBr salt
of the triaryl base was prepared independently and could
be shown to effect the bromination of 1 under the photo-
catalytic reaction conditions. These observations strongly
support our mechanistic proposal. The photocatalyst can
oxidize bromide ions to radicals,20 which then react with
bromide ions exergonically to form Br2 (–18.1 kcal/mol),
consistent with the Meyer study.18 The Br2•– can then be-
come oxidized by the ruthenium(III) photocatalyst to mo-
lecular bromine, which was also found to be exergonic by
We have recently disclosed two DFT studies of photo-
catalytic C–H functionalization processes, in one of which
the C-2 malonation of indoles was studied in detail (see the
16,17
Supporting Information).
Herein, we discuss our pro-
posed mechanism for double C–H functionalization of N-
methylindole (Scheme 3) with energies calculated at the
B3LYP-D3BJ/6-311+G(d,p)/DMF(IEF-PCM) level of theory.
•
–
H
–
13.9 kcal/mol. We were unable to obtain a proper transi-
CO2Et
4-MeOC6H4NPh2
tion state for the bromination of 1 with Br , but a PES scan
2
EtO2C
CO2Et
H
N
2
CO Et
revealed an approximate potential energy barrier of 6.8
kcal/mol for this reaction. Followed by HBr elimination, the
transformation from 1 to 2 was exergonic by –19 kcal/mol.
In conclusion, we have demonstrated a novel photocata-
lytic double C–H functionalization of C-2 and C-3 positions
of indoles. Moreover, we have studied mechanistic details
of the transformation by DFT and by careful examination of
the reaction progress and byproduct formation. The results
suggest that two independent photocatalytic processes oc-
cur to produce the observed difunctionalization and that
the secondary reaction occurs through oxidation of bro-
mide ions formed during the reaction progress. This can
generate molecular bromine amenable to C-3 bromination.
The high sensitivity of the chemical yields toward electron-
ic effects underscores the challenges involved in achieving
selective C–H multifunctionalizations. Studies to develop
the photocatalytic C–H bromination chemistry further are
under way and will be disclosed in the near future.
SET
ΔG‡ = 8.9
ΔG = –1.3
Me
ΔG = –17.2
4
-MeOC6H4NPh2
H
CO2Et
N
N
H
2
CO Et
Me
Me
Br
CO2Et
2
Br
ΔG = –9.5
2
N
CO Et
HBr
ΔE‡ =6.8
Me
CO2Et
ΔG = –19.0
1
HBr
N
CO Et
2
Me
ΔG = –13.9
ΔG = –18.1
Br2
SET
Br2
Br
+
Br
RuII
RuIII
Scheme 3 Experimentally supported, proposed reaction mechanism
for the photocatalytic double C–H functionalization of 1-methylindole,
calculated using B3LYP-D3BJ/6-311+G(d,p)/DMF(IEF-PCM)
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U. Erdenebileg et al.
Letter
Acknowledgment
(14) Peña-López, M.; Rosas-Hernández, A.; Beller, M. Angew. Chem.
Int. Ed. 2015, 54, 5006.
The authors would like to acknowledge generous funding for this
project from the Department of Chemistry at UiT The Arctic Universi-
ty of Norway, and provision of computational resources from NOTUR
(
15) General Procedure
An oven-dried 10 mL round-bottom flask was equipped with a
rubber septum and magnetic stirrer and was charged with the
heteroaromatic substrate (0.5 mmol, 1.0 equiv), tris(2,2′-bipyr-
idyl)ruthenium(II) chloride hexahydrate (5.0 μmol, 3.70 mg, 1.0
mol%), 4-methoxyphenyl-N,N-diphenylamine (1.0 mmol, 0.274
g, 2.0 equiv), diethyl bromomalonate (1.0 mmol, 0.239 g, 2.0
equiv), and DMF (2.0 mL). The mixture was degassed by the
freeze-pump-thaw method, and the reaction vessel was filled
with argon. A 1 W blue light-emitting diode (LED) strip was
placed around the reaction vessel at a distance of approximately
(grant number NN4654K).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588719. Detailed experimental
procedures, characterization and spectra, as well as computational
details and xyz-coordinates, are included.
S
u
p
p
o
nrtIo
i
g
f
rm oaitn
S
u
p
p
ortioIgnfmr oaitn
2–4 cm. The reaction was stopped by removing the LED lamps,
and the mixture was poured into a separatory funnel containing
EtOAc (10 mL) and water (10 mL). The layers were separated,
and the aqueous layer was extracted with EtOAc (2 × 10 mL).
The combined organic phases were washed with brine (10 mL),
dried (anhydrous Na SO ), filtered, and concentrated on a
rotary evaporator. The residue was purified by preparative HPLC
on a C18 column, using water and MeCN eluent systems. Appro-
priate fractions were collected, frozen and lyophilized to afford
the products as pure compounds.
References and Notes
(1) Fagnoni, M.; Dondi, D.; Ravelli, D.; Albini, A. Chem. Rev. 2007,
2
4
107, 2725.
(2) Hoffmann, N. Chem. Rev. 2008, 108, 1052.
(3) Wang, C.; Qin, J.; Shen, X.; Riedel, R.; Harms, K.; Meggers, E.
Angew. Chem. Int. Ed. 2016, 55, 685.
(
(
4) Xuan, J.; Xiao, W.-J. Angew. Chem. Int. Ed. 2012, 51, 6828.
5) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W.
Chem. Soc. Rev. 2016, 45, 546.
Analytical Data for Compound 2
IR (neat): 3063 (w), 2981 (m) 2937 (m), 1736 (s), 1613 (w),
1467 (s), 1392 (m), 1367 (s), 1344 (m), 1308 (s), 1266 (s), 1240
(
(
(
(
6) DiRocco, D. A.; Dykstra, K.; Krska, S.; Vachal, P.; Conway, D. V.;
(
s), 1210 (s), 1175 (s), 1150 (s), 1108 (m), 1095 (m), 1031 (s),
Tudge, M. Angew. Chem. Int. Ed. 2014, 53, 4802.
7) Furst, L.; Matsuura, B. S.; Narayanam, J. M. R.; Tucker, J. W.;
Stephenson, C. R. J. Org. Lett. 2010, 12, 3104.
–1 1
9
7
5
6
1
1
3
46 (m), 853 (w), 739 (s) cm . H NMR (400 MHz, CDCl ): δ =
3
.55 (d, J = 7.8 Hz, 1 H), 7.34–7.28 (m, 2 H), 7.22–7.18 (m, 1 H),
.35 (s, 1 H), 4.33–4.21 (m, 4 H), 3.81 (s, 3 H), 1.30 (t, J = 6.9 Hz,
8) Hari, D. P.; Schroll, P.; König, B. J. Am. Chem. Soc. 2012, 134,
13
H). C NMR (100 MHz, CDCl ): δ = 166.7 (2 CO), 137.3, 128.5,
3
2958.
26.3, 123.3, 120.5, 119.5, 109.7, 93.6, 62.4 (2 CH ), 50.3, 32.0,
2
+
9) Nguyen, J. D.; D’Amato, E. M.; Narayanam, J. M. R.; Stephenson,
+
4.1 (2 CH ). HRMS: m/z calcd for C16H19O NBr [M + H] :
3
4
C. R. J. Nat. Chem. 2012, 4, 854.
68.0492; found: 368.0491.
(
10) O’Hara, F.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc. 2013,
35, 12122.
11) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem. Int. Ed.
012, 51, 8960.
(
(
16) Demissie, T. B.; Hansen, J. H. J. Org. Chem. 2016, 81, 7110.
17) Demissie, T. B.; Ruud, K.; Hansen, J. H. Organometallics 2015, 34,
1
(
4
218.
18) Li, G.; Ward, W. M.; Meyer, G. J. J. Am. Chem. Soc. 2015, 137,
321.
2
(
(
(
(
(
12) Demissie, T. B.; Hansen, J. H. Dalton Trans. 2016, 45, 10878.
13) Romero, N. A.; Margrey, K. A.; Tay, N. E.; Nicewicz, D. A. Science
8
19) Pathak, R.; Nhlapo, J. M.; Govender, S.; Michael, J. P.; van Otterlo,
W. A. L.; de Koning, C. B. Tetrahedron 2006, 62, 2820.
20) Hering, T.; Meyer, A. U.; König, B. J. Org. Chem. 2016, 81, 6927.
2015, 349, 1326.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F