Intermolecular Photocatalytic C-H Functionalization of Electron-Rich Heterocycles with Tertiary Alkyl Halides

Article abstract of DOI:10.1055/s-0035-1561320

The coupling of tertiary alkyl halides with electron-rich arenes is promoted by visible-light photoredox catalysis. Tris[2-phenylpyridinato-C²,N]iridium(III) [Ir(ppy)₃] was the optimal catalyst, enabling direct reduction of the halide from the excited state, and thereby eliminating the requirement for a stoichiometric electron donor. High yields were obtained when the aromatic component was used in excess, although equimolar amounts afforded only slightly diminished yields. The reaction tolerates a number of functional groups, including allyl, ester, amide, or carbamate. The efficiency of this reaction has been improved through demonstration of scale-up in flow, and a new substituted Ir(ppy)₃ derivative was isolated and characterized.

Full text of DOI:10.1055/s-0035-1561320

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 754–758
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754
E. C. Swift et al.
Cluster
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Intermolecular Photocatalytic C–H Functionalization of Electron-
Rich Heterocycles with Tertiary Alkyl Halides
Ir(ppy)3
(1 mol %)
Elizabeth C. Swift
CO2R2
CO2R2
E
R3
R1
R1
Theresa M. Williams
+
H
Corey R. J. Stephenson*
Br
E
blue LEDs
R3
X
X
Department of Chemistry, University of Michigan,
930 N. University Ave, Ann Arbor, MI 48109, USA
crjsteph@umich.edu
E = CO2R2, CN
3 = 1° or 2° alkyl,
allyl, Bn
quaternary
X = NH, NR, O, S
1 = halogen,
alkyl
carbon center
25 examples,
batch and flow
Yields 35–89%
R
R
Received: 29.10.2015
Accepted after revision: 16.12.2015
Published online: 08.01.2016
moieties, all of which are important heterocyclic cores in
molecules of biological interest. Despite this, a method for
photochemical addition of tertiary malonyl radicals to elec-
tron-rich aromatics to form quaternary carbon centers has
not been reported.6 With few exceptions,7 additions of this
type still rely on traditional approaches using stoichiomet-
ric reagents.8
DOI: 10.1055/s-0035-1561320; Art ID: st-2015-r0850-c
Abstract The coupling of tertiary alkyl halides with electron-rich
arenes is promoted by visible-light photoredox catalysis. Tris[2-phen-
ylpyridinato-C2,N]iridium(III) [Ir(ppy)3] was the optimal catalyst, en-
abling direct reduction of the halide from the excited state, and thereby
eliminating the requirement for a stoichiometric electron donor. High
yields were obtained when the aromatic component was used in ex-
cess, although equimolar amounts afforded only slightly diminished
yields. The reaction tolerates a number of functional groups, including
allyl, ester, amide, or carbamate. The efficiency of this reaction has
been improved through demonstration of scale-up in flow, and a new
substituted Ir(ppy)3 derivative was isolated and characterized.
To address this challenge, we sought to extend our pre-
viously described C–H functionalization reaction of elec-
tron-rich aromatic heterocycles with diethyl bromom-
alonate9 to tertiary bromomalonates as coupling partners.
We were motivated by the utility of substituted malonates
in providing additional functional-group handles for fur-
ther synthetic manipulation. For this reason, substituted
malonate esters have been used as building blocks in the
synthesis of complex indole alkaloids,10 as well as pharma-
ceutical agents.11 For example, actinophyllic acid and the
core of tronocarpine have been prepared from indole inter-
mediates with malonates (Scheme 1). Furthermore,
malonate esters themselves have been shown to possess
antimycobacterial properties12 and to act as ion-channel-
modulating agents (Scheme 1).13 We therefore sought to
elicit the formation of reactive tertiary radical intermedi-
ates that would undergo addition reactions to produce
these valuable substituted malonate esters. Building on re-
cent mechanistic studies,14 we sought to apply the knowl-
edge gained from our model system to engage more chal-
lenging substrates and thereby broaden the utility of the re-
action.
Key words photoredox, catalysis, alkylation, C–H functionalization,
quaternary carbon, flow reaction
In the last decade, interest in visible-light photoredox
catalysis has fostered the development of many new organ-
ic transformations under mild, selective, and environmen-
tally benign conditions.1 Less well studied are reactions that
achieve the intermolecular construction of quaternary car-
bon centers.2 Reactive radical intermediates have been
shown to be competent in the formation of sterically
crowded structures;3 therefore, the use of visible-light-ac-
tive catalysts for the efficient production of these radicals
would provide an ideal manifold for this bond construction.
Indeed, several useful examples have emerged recently of
electron-rich radical additions to electron-deficient ole-
fins.4 Conversely, mild conditions for tertiary radical addi-
tions to electron-rich aromatics are lacking. This transfor-
mation is challenging due the need for a tertiary electron-
deficient radical;5 however, the use of electron-deficient
radical precursors, such as bromomalonates, might provide
electronically matched coupling partners, leading to qua-
ternary carbons bearing indole, pyrrole, thiophene, or furan
During reaction optimization, several key observations
were made. Evaluation of a range of visible-light photocata-
lysts revealed that product yields generally correlated with
the redox potential. Ru(bpy)3Cl2, the most weakly reducing
III/II*
catalyst tested (E1/2
= –0.81 V vs. SCE),15 gave only a 7%
yield of the desired product over 24 hours (Table 1, entry 1),
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 754–758

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E. C. Swift et al.
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Table 1 Optimization of Coupling to Indole
R3
H
catalyst
X
X = NR, O, S
Ir(ppy)3
blue LEDs
CO2R2
(1 mol%)
additive
(1 equiv)
CO2R2
E
R1
R3
CO2R2
Me
Me
Br
E
R1
E = CO2R2, CN
CO2Et
CO2Et
R1
E
Br
CO2Et
CO2Et
X
N
N
blue LEDs,
r.t., 24 h
H
quaternary carbon
center
H
7
5 (5 equiv)
Entry Catalyst
6 (1 equiv)
Examples in alkaloid synthesis:
NH
Additive
Solvent
Yielda (%)
1
Ru(bpy)3Cl2
2,6-lutidine
2,6-lutidine
2,6-lutidine
Ph2N(PMP)b
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
MeCN
MeCN
MeCN
DMAc
MeCN
MeCN
MeCN
MeCN
7
20
29
80
94
66
44
46
O
N
H
HN
2
Ir(dF(CF3)ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)3
CO2Me
N
3
HO2C
H
OH
O
4
HO
2
1
5
(–)-actinophyllic acid
tronocarpine core
6d
7e
8e,f
Ir(ppy)3
Examples as bioactive molecules:
H
Ir(ppy)3
N
Ir(ppy)3
Me
CO2Et
CO2Et
a NMR yield based on PhTMS as internal standard.
b 4-Methoxy-N,N-diphenylaniline (2 equiv).
c N,N-Dimethylacetamide.
i
S
d 2 equiv of indole.
CO2 Pr
e 1 equiv indole.
i
CO2 Pr
N
f 5 equiv of bromomalonate.
H
Cl
3
4
antimycobacterial agent
MIC 16 mg/mL
ion-channel modulator
10 mM activity
With optimized conditions in hand, we turned to evalu-
ating the scope of the transformation. By employing various
substituted bromomalonates, we found that the reaction
tolerates a range of functional groups and steric environ-
ments (Scheme 2). For example, we found an allyl group
was well tolerated. This example is notable in that indole
functionalization proceeds in good yield despite the possi-
bility of an atom-transfer radical addition to the olefin,21
which might also lead to polymerization.22 Additionally,
substrates with α-secondary centers, such as diethyl 2-bro-
mo-2-cyclohexylmalonate, could be coupled efficiently.
Various benzyl groups were tolerated, as well as the hetero-
cycle Boc-piperidine, providing the corresponding products
10–13 in good yields. A bromomalonate with a longer alkyl
chain and a TBS-protected alcohol group also underwent
coupling, to produce indole 14.23 A seven-membered bro-
molactone and mixed malonate provided low yields of the
desired coupled product under normal reaction conditions;
however, increasing the amount of heterocycle to 20 equiv-
alents improved the yield, providing lactone 24 in 64% yield
and the alkylated pyrrole 25 in 42% yield. No reaction was
observed with bromomalononitriles (not shown).
Scheme 1 Alkylation with tertiary alkyl halides
whereas
bis[2-(2,4-difluorophenyl)-5-(trifluoromethyl)-
pyridinato-C2,N](4,4′-di-tert-butyl-2,2′-bipyridinato-N,N)iridi-
um(III) hexafluorophosphate {Ir[dF(CF3)ppy]2(dtbbpy)PF6}
IV/III*
(E1/2
= –0.89 V vs. SCE)16 and bis[2-phenylpyridinato-
C2,N](4,4′-di-tert-butyl-2,2′-bipyridinato-N,N)iridium(III)
hexafluorophosphate [Ir(ppy)2(dtbbpy)PF6] (E1/2IV/III* = –0.96
V vs SCE)17 gave yields of 20% and 29%, respectively (entries
2 and 3). By using the reductive quenching cycle of
Ir(ppy)2(dtbbpy)PF6 (E1/2III/II = –1.51 V vs. SCE) with the addi-
tion of two equivalents of 4-methoxy-N,N-diphenylaniline
as a reductive quencher, an 80% yield was obtained (entry
4). fac-Tris[2-phenylpyridinato-C2,N]iridium(III) [Ir(ppy)3],
the most strongly reducing catalyst tested (E1/2
IV/III*
= –1.73
V vs. SCE),18 provided the best results under our condi-
tions.19 This catalyst has a suitably strong reduction poten-
tial in the excited state to produce reactive radical interme-
diates directly from a number of alkyl halides without the
need for an exogenous electron donor.20 The use of an ex-
cess of indole improved the overall yield, with five equiva-
lents providing the desired product in 94% yield (entry 5).
Notably, the excess indole can be recovered, as it is not con-
sumed in the reaction. The number of equivalents of indole
could be lowered with a concomitant decrease in yield; a
44% yield was obtained by using equimolar amounts of the
coupling partners (entry 7). The reaction did not proceed in
the absence of light or catalyst.
When evaluating the scope of the reaction with respect
to heterocycles, we found that various N-substituents and
protecting groups were tolerated, with N-methylindole as
well as Boc-pyrrole giving the corresponding coupling
products (Scheme 2).23 For some less electron-rich aromat-
ics, such as Boc-pyrrole, extended reaction times were re-
quired; alternatively, we found that increasing the intensity
of the light strips from 1 W to 4 W also accelerated the reac-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 754–758

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E. C. Swift et al.
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Ir(ppy)3 (1 mol%)
2,6-lutidine
R
CO2Me
R
CO2Me
+
E
R
Br
E
R
X
MeCN, r.t., 24 h
1 W blue LEDs
X
yielda
CO2Me
CO2Me
Ar
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
N
N
H
N
N
H
H
H
N
H
10, Ar = Ph; 69%
OTBS
NBoc
11, Ar = 3-ClC6H4; 58%
12, Ar = 4-CF3C6H4; 51%
8, 57%b
R2
9, 53%b
13, 77%b
14, 89%b
CO2Me
CN
R
O
MeO2C
CO2Et
CO2Et
Me
CO2Et
CO2Et
R3
CO2Et
CO2Et
Me
N
CO2Et
CO2Et
Me
O
H
N
N
H
Me
NR1
N
N
H
25, 42%d
N
Me
R
H
24, 35%, 64%c
7, R1 = R2 = R3 = H; 83%
15, R1 = Me; R2 = R3 = H; 52%
16, R3 = F; R2 = R1 = H; 78%
17, R2 = Br; R1 = R2 = H; 66%
20, R = Me; 68%
21, R = CH2CH2Br; 45%
22, R = CH2CH2OH; 48%
18, R = H; 65%
19, R = Boc; 83%e
CO2Et
CO2Et
23, 63%
CO2Et
EtO2C
Me
S
O
Me
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Me
CO2Me
Cl
CO2Et
Me
N
4, 68%f
N
H
S
O
S
Me
Me
Ph
SK/BK/IK ion-channel modulator,
10 mM activity
26, 76%b
29, 80%b
28, 77%e
30, 78%e
27, 45%
Scheme 2 Coupling of substituted bromomalonates with N, O, and S-heterocycles. Reagents and conditions: Ir(ppy)3 (1 mol%), 2,6-lutidine (1 equiv),
malonate (1 equiv), heterocycle (5 equiv), MeCN, 1 W blue LEDs, r.t., 24 h. a Isolated yields after column chromatography. b 4 W LEDs. c 20 equiv indole.
d 20 equiv pyrrole. e 48 h, DMA. f 10 equiv thiophene.
tion. In line with the mild nature of photoredox transfor-
mations, a range of substituents on the indole were well
tolerated, including alkyl or aryl bromides, aryl fluorides, or
free hydroxy groups. Blocking the 2-position of the indole
with a methyl ester results in coupling at the 3-position.
Other heterocycles were evaluated, and it was found that
benzofuran, benzothiophene, thiophene, 7-azaindole, pyr-
role (both free and N-Boc-protected) and N-methylpyridin-
2(1H)-one all underwent functionalization in good yields.
Pyridones can be converted into the corresponding pyri-
dines by several known routes.24
To highlight the utility of this method, we attempted to
combine a complex bromomalonate coupling partner with
a nonfunctionalized heteroaromatic compound to give the
bioactive malonate 4. This compound and related structures
are known to modulate Ca2+-activated K+ channels with
subtypes SK/IK/BK.13a They show therapeutic potential in
cardiovascular and neurological diseases, where regulation
of these channels is key.13b,c To prepare malonate 4, we sub-
jected thiophene to our standard conditions in the presence
of diethyl 2-bromo-2-(2-chlorobenzyl)malonate. This reac-
tion produced the substituted thiophene product in 68%
yield. In comparison, the patented preparation of 4 pro-
ceeds from ethyl 2-thienylacetate; our route therefore rep-
resents an alternative disconnection and does not require
prior functionalization of thiophene. This highlights the
utility of this method in providing greater flexibility in the
overall synthetic design of bioactive targets. Next, we at-
tempted to adapt the C–H functionalization to continuous-
flow processing to improve the efficiency of the transfor-
mation on a larger scale.
Photochemistry in flow has been known to display a
number of benefits compared with batch processing, in-
cluding decreased reaction times, improved conversions,
and improved safety upon scale-up.25 On performing the
reaction in a flow apparatus with an internal volume of
1.95 mL, we found that the reaction was complete after a 40
minute residence time (Table 2, entry 1). This corresponded
to a conversion rate of 1.0 mmol per hour, permitting the
reaction of one gram of material in a total time of four
hours, representing a twofold increase in reaction through-
put. In comparison, we were able to obtain full conversion
in a batch reaction at a one-gram scale in eight hours with a
36-W array of blue LEDs (entry 2). The recovered material
revealed the formation of Ir(ppy)3 functionalized with three
equivalents of diethyl 2-methylmalonate (31).14 We per-
formed another reaction using only the functionalized 31
as catalyst, which gave comparable yields in the same time
as nonfunctionalized Ir(ppy)3 (entry 3), demonstrating that
the alkylated catalyst is a competent catalyst for this reac-
tion.
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E. C. Swift et al.
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Table 2 Comparison of Batch and Flow Processes
catalyst (1 mol%)
2,6-lutidine (1 equiv)
5
6
7
+
36 W blue LEDs, MeCN, r.t.
Entry
Catalyst
Process
Conv. (mmol/h)
Yielda (%)
1b
2
Ir(ppy)3
Ir(ppy)3
flow
1.0
0.5
70
78
Me
EtO2C
EtO2C
batch
Ir
N
3
31
batch
0.5
78
3
31
isolated from reaction mixture,
entry 2
a Isolated yields after column chromatography.
b Residence time 40 min; DMA solvent.
In conclusion, we have developed a mild, functional-
group-tolerant C–H alkylation reaction of electron-rich het-
erocycles with tertiary bromomalonates for the preparation
of quaternary carbon centers. The reaction conditions em-
ploy the photocatalyst Ir(ppy)3. In this report, we have
demonstrated that the intermolecular coupling of complex
bromomalonates represents a new approach to the chal-
lenge of forming quaternary carbon centers. We have high-
lighted the utility of this method through the preparation
of a biologically active molecule and by its application to a
flow reactor. Efforts to apply this methodology in alkaloid
synthesis are currently underway.
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Acknowledgment
The authors thank Dr. Bryan Matsuura, Mr. Joel Beatty, Mr. Mitchell
Keylor, and Dr. John Nguyen, for their helpful discussions and sugges-
tions. This material is based upon work supported by the National
Science Foundation Graduate Research Fellowship Program (Grant
No. DGE 1256260). Financial support for this research from the NIH-
NIGMS (R01-GM096129), the Alfred P. Sloan Foundation, the Camille
Dreyfus Teacher-Scholar Award Program, Eli Lilly, Novartis, and the
University of Michigan is gratefully acknowledged.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561320.
lyzed addition of
a tertiary radical to benzofuran, see:
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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for 24 h. The resulting mixture was diluted with EtOAc and
extracted with H2O. The aqueous layer was extracted with
EtOAc (2 × 5 mL). The combined organic layers were washed
with brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by chromatography (silica gel, 0–5%
EtOAc–hexane) to give a white solid; yield: 97 mg (83%);
Rf = 0.36 (10% EtOAc–hexane). IR (neat): 3372, 2972, 1732,
1707, 1454, 1263 cm–1. 1H NMR (400 MHz, CDCl3): δ = 9.08 (s, 1
H), 7.58 (d, J = 7.9 Hz, 1 H), 7.37 (d, J = 7.6 Hz, 1 H), 7.18 (t, J = 7.1
Hz, 1 H), 7.09 (t, J = 7.1 Hz, 1 H), 6.47 (s, 1 H), 4.27–4.23 (m, 4 H),
1.95 (s, 3 H), 1.28 (t, J = 7.1 Hz, 6 H). 13C NMR (176 MHz, CDCl3):
δ = 170.4, 136.2, 134.7, 127.5, 122.2, 120.5, 119.7, 111.0, 101.4,
62.2, 54.3, 21.2, 14.0. HRMS (ESI): m/z [M + H]+ calcd for C16H20NO4:
290.1387; found: 290.1386.
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Q.; Covington, M. B.; Pitts, W.; Kim, S.-H.; Decicco, C. P. Bioorg.
Med. Chem. Lett. 2007, 17, 266.
Dimethyl (4-{[tert-Butyl(dimethyl)silyl]oxy}butyl)(1H-indol-
2-yl)malonate (14)
Yellow oil; yield: 0.15 g (89%); Rf = 0.6 (20% EtOAc–hexane). IR
1
(neat): 3426, 2951, 2356, 1729, 1456, 1254 cm–1. H NMR (700
MHz, CDCl3): δ = 9.60 (s, 1 H), 7.58 (d, J = 7.9 Hz, 1 H), 7.40 (d, J =
8.1 Hz, 1 H), 7.20 (t, J = 7.6 Hz, 1 H), 7.11 (t, J = 7.5 Hz, 1 H), 6.44
(s, 1 H), 3.78 (s, 6 H), 3.57 (t, J = 6.3 Hz, 2 H), 2.45–2.43 (m, 2 H),
1.54 (quintet, J = 7.1 Hz, 2 H), 1.29–1.25 (m, 2 H), 0.87 (s, 9 H),
0.02 (s, 6 H). 13C NMR (176 MHz, CDCl3): δ = 170.6, 135.8, 133.9,
127.7, 122.1, 120.5, 119.9, 111.3, 101.3, 62.6, 58.5, 53.2, 36.5,
32.8, 26.0, 21.1, 18.3, –5.2. HRMS (ESI): m/z [M + H]+ calcd for
(12) Mahboobi, S.; Kuhr, S.; Meindl, W. Arch. Pharm. (Weinheim, Ger.)
1994, 327, 611.
C23H36NO5Si: 434.2357; found: 434.2355.
Methyl 3-(1H-Indol-2-yl)-2-oxooxepane-3-carboxylate (24)
Purple oil; yield: 40 mg (35%); Rf = 0.25 (30% EtOAc–hexane). IR
(neat): 3317, 2943, 2360, 1738, 1696, 1454, 1224 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 8.72 (s, 1 H), 7.59 (d, J = 7.9 Hz, 1 H), 7.38
(dd, J = 8.2, 0.7 Hz, 1 H), 7.20 (td, J = 7.6, 1.1 Hz, 1 H), 7.11 (td, J =
7.5, 0.8 Hz, 1 H), 6.50 (d, J = 1.3 Hz, 1 H), 4.19 (ddd, J = 12.7, 7.6,
1.9 Hz, 1 H), 4.08 (ddd, J = 12.7, 8.1, 1.8 Hz, 1 H), 3.78 (s, 3 H),
2.72 (dt, J = 14.7, 5.8 Hz, 1 H), 2.38 (dt, J = 14.7, 6.6 Hz, 1 H), 2.06
(quintet, J = 6.1 Hz, 2 H), 1.94–1.88 (m, 1 H), 1.85–1.80 (m, 1 H).
13C NMR (176 MHz, CDCl3): δ = 171.6, 169.6, 136.7, 133.6, 127.7,
122.8, 120.8, 120.2, 111.4, 102.3, 69.5, 59.8, 53.5, 31.3, 28.1,
24.1. HRMS (ESI): m/z [M + H]+ calcd for C16H18NO4: 288.1230;
found: 288.1299.
(13) (a) Beyer, J.; Jensen, B. S.; Strøbaek, D.; Christophersen, P.;
Teuber, L. WO 037422, 2000. (b) Ledoux, J.; Werner, M. E.;
Brayden, J. E.; Nelson, M. T. Physiology (Bethesda) 2006, 21, 69.
(c) Dolga, A. M.; Culmsee, C. Front. Pharmacol. 2012, 3, 196.
(14) Devery, J. J. III.; Douglas, J. J.; Nguyen, J. D.; Cole, K. P.; Flowers, R.
A. II.; Stephenson, C. R. J. Chem. Sci. 2015, 6, 537.
(15) (a) Kalyanasundaram, K. Coord. Chem. Rev. 1982, 46, 159.
(b) Juris, A.; Balzani, V.; Belser, P.; von Zelewsky, A. Helv. Chim.
Acta 1981, 64, 2175.
(16) Lowry, M. S.; Goldsmith, J. I.; Slinker, J. D.; Rohl, R.; Pascal, R. A.;
Malliaras, G. G.; Bernhard, S. Chem. Mater. 2005, 17, 5712.
(17) 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.
Diethyl
Methyl(1-methyl-2-oxo-1,2-dihydropyridin-3-
yl)malonate (29)
(18) Flamigni, L.; Barbieri, A.; Sabatini, C.; Ventura, B.; Barigelletti, F.
Top. Curr. Chem. 2007, 281, 143.
Brown oil; yield: 0.11 g (80%); Rf = 0.5 (20% EtOAc–hexane). IR
1
(neat): 2982, 1724, 1648, 1597, 1558, 1228 cm–1. H NMR (400
(19) The reaction was found to proceed in a number of solvents; see
Supporting Information for details.
(20) Nguyen, J. D.; D’Amato, E. M.; Narayanam, J. M. R.; Stephenson,
C. R. J. Nat. Chem. 2012, 4, 854.
(21) Nguyen, J. D.; Tucker, J. W. Konieczynska M. D.; Stephenson, C. R.
J. J. Am. Chem. Soc. 2011, 133, 4160.
(22) Fors, B. P.; Hawker, C. J. Angew. Chem. Int. Ed. 2012, 51, 8850.
(23) Diethyl 1H-Indol-2-yl(methyl)malonate (7); Typical Proce-
dure
MHz, CDCl3): δ = 7.24–7.21 (m, 2 H), 6.08 (t, J = 6.9 Hz, 1 H),
4.24–4.13 (m, 4 H), 3.47 (s, 3 H), 1.74 (s, 3 H), 1.20 (t, J = 7.1 Hz,
6 H). 13C NMR (176 MHz, CDCl3): δ = 170.7, 161.2, 137.5, 135.4,
131.7, 105.0, 61.6, 57.4, 37.8, 20.8, 14.0. HRMS (ESI): m/z [M +
Na]+ calcd for C14H19NNaO5: 304.1155; found: 304.1155.
(24) Smith, F. X.; Evans, G. G. Tetrahedron Lett. 1972, 13, 1237.
(25) (a) For a recent review, see: Su, Y.; Straathof, N. J. W.; Hessel, V.;
Noël, T. Chem. Eur. J. 2014, 20, 10562. For selected examples, see.
(b) Bou-Hamdan, F. R.; Seeberger, P. H. Chem. Sci. 2012, 3, 1612.
(c) Andrews, R. S.; Becker, J. J.; Gagné, M. R. Angew. Chem. Int. Ed.
2012, 51, 4140. (d) Tucker, J. W.; Zhang, Y.; Jamison, T. F.;
Stephenson, C. R. J. Angew. Chem. Int. Ed. 2012, 51, 4144.
(e) Beatty, J.; Stephenson, C. R. J. J. Am. Chem. Soc. 2014, 136,
10270.
A 7 mL vial equipped with magnetic stirrer bar was charged
with diethyl-2-bromo-2-methylmalonate (1.0 equiv, 0.40
mmol, 0.10g), 2,6-lutidine (1.0 equiv, 0.40 mmol, 43 mg),
Ir(ppy)3 (1 mol%, 4.0 μmol, 2.6 mg), and indole (5.0 equiv, 2.0
mmol, 0.23 g). Anhyd MeCN (0.5 mL, 0.8 M) was added, and the
mixture was sparged with N2 for 15 min. It was then sur-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 754–758