S
1
Supp
orting
Information
Three
-
C
omponent
C
ross
-
E
lectrophile
C
oupling:
Regioselective E
lectrochemical
D
ialkylation of
A
lkenes
Lingxiang Lu,
†
Yi Wang,
†
Wendy Zhang,
‡
Wen Zhang,
†
Kimberly A. See,
‡
Song Lin*
,†
†
Department of Chemistry and
Chemical Biology, Cornell University, Ithaca, New York 14853, United States
‡
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125,
United States
*
E
mail
: songlin@cornell.edu
Contents:
S1. General Information
................................
................................
................................
................................
...............
S
2
S2. General Pro
cedure for Electrochemical Dialkylation of Alkenes
................................
................................
............
S
3
S3. Optimization of Reaction
Conditions
................................
................................
................................
.....................
S
4
S4. Cyclic Voltammetry Studies
................................
................................
................................
................................
....
S
5
S5. Voltage Profile Measurements
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................................
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...............................
S
8
S6. Substrate Scope
................................
................................
................................
................................
.....................
S
9
S7. Characterization of Products
................................
................................
................................
................................
S
12
S8. Mechanistic Studies
................................
................................
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................................
.............
S
33
S9. Copies of NMR Spectra
................................
................................
................................
................................
........
S
37
S10. Reaction Reproduction Report
................................
................................
................................
.........................
S
150
S11. References
................................
................................
................................
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.......................
S
151
S
2
S1. General
I
nformation
All reactions were carried out in oven
-
dried glassware
with magnetic stirring
under nitrogen
.
1,2
-
Dimethoxyethane
(DME)
and tetrahydrofuran (THF) were
dried over molecular sieves
before use
.
Mg anode and graphite cathode were
polished before use
.
Since alkyl bromides decompose over time during storage, the use of freshly prepared/distilled
substrates is recommended.
All
other
chemicals
were used as received.
Flash column chromatograph
y
w
as
performed using silica gel
(230−400 mesh) from SiliCycle.
Nuclear magnetic resonance (NMR) spectra were measured
on Bruker
NMR instruments
(
1
H at
5
00
MHz
,
13
C
{
1
H}
at 1
26
MHz
,
1
9
F
at
47
0
MHz
,
19
F{
1
H} at 376 MHz,
31
P at 202 MHz
).
Data for
1
H NMR spectr
a
a
re reported as follows: chemical shift
δ
(
ppm) referenced to
CHCl
3
(
7
.2
6
ppm)
, multiplicity
(
s = singlet,
d = doublet,
t = triplet,
q = quartet,
brs = broad singlet,
dd = doublet of doublets,
t
d
= triplet of
doublets
,
m = multiplet
), coupling constant
J
(Hz), and integration. Data for
13
C{
1
H} NMR
spectr
a
a
re
reported
as follows:
chemical shift
δ
(
ppm) referenced to CDCl
3
(77.16 ppm)
,
multiplicity (null = singlet,
d = doublet,
q = quartet)
, and
coupling constant
J
(Hz)
.
Data for
19
F
and
31
P
NMR spectr
a
are
reported in terms of chemical shift
δ
(
ppm)
and
multiplicity (s = singlet,
t
=
triplet
,
m = multiplet
)
.
Data for
19
F{
1
H} NMR spectra are reported in terms of chemical
shift
δ
(
ppm).
High
-
resolution mass spectra (HRMS) were recorded on Thermo Scientific
Exactive Orbitrap
mass
spectrometer
s
with
direct analysis in real time
(DART) or electron
impact
ionization
(EI)
.
S
3
S2. G
eneral
P
rocedure for
E
lectrochemical
D
ialkylation of
A
lkenes
In a nitrogen
-
regulated glovebox, an oven
-
dried 5
-
m
L
ElectraSyn vial was charged with tetrabutylammonium
perchlorate (
TBA
ClO
4
, 2.0 mmol, 2.0
equiv
) and a stir bar. Then, a solution of alkene (1.0 mmol, 1.0
equiv
), tertiary
alkyl bromide (2.0 mmol, 2.0
equiv
),
and
primary alkyl bromide (1.0 mmol, 1.0
equiv
) in 4.0 m
L
of anhydrous DME
was added
and t
he
reaction mixture
was stirred to dissolve the
elec
trolyte
.
After that, t
he ElectraSyn vial and cap
equipped with anode (Mg plate) and cathode (graphite plate) were screwed tight, transferred out of the glovebox,
and mounted onto the ElectraSyn 2.0 device.
A nitrogen balloon was attached to the cap and the
reaction mixture
was electrolyzed
with
magnetic stirring
(stirring rate: 1200 rpm
)
at a constant current of 2.5 mA until passing 3.0
F/mol of charge at room temperature
(22 °C)
.
Upon
complet
ion
of electrolysis
,
t
he
reaction
mixture was passed
through a p
lug
of silica gel (ca. 8 cm
thick
) and eluted with 125 m
L
of 20% Et
2
O in hexanes (the volume includes
that
of
the solvent used to rinse the reaction vial
and electrodes
). The filtrate was concentrated under reduced pressure
and the crude product
was purified by flash column chromatography (silica gel) to afford the desired product.
Fig
ure
S
1
.
E
lectrochemical setup for
alkene
dialkylation
.
(A)
Rubber septum,
ElectraSyn cap, and
electrodes
.
(B)
ElectraSyn cap equipped with
electrodes
.
(C)
ElectraSyn vial with
electrolyte
and stir bar.
T
he screw thread
was
covered
with
polytetrafluoroethylene (PTFE)
tape
.
(D)
Reaction mixture before electrolysis.
(E)
Reaction mixture after
electrolysis.
(F)
Filtration to remove electrolyte and
magnesium salts.
S
4
S3. Optimization
of
R
eaction
C
onditions
The reaction optimization was shown in Table
S
1.
The main identifiable side product
61
arose from hydroalkylation
of
1
with tertiary alkyl bromide
2
, presumably from interception of carbanion interm
ediate
F
(see
Scheme
2
A
in the
main text for
the
structure) by
the tetrabutylammonium electrolyte
(
via Hofmann elimination
)
,
2
(
via E2 elimination
),
or
residual water
(via protonation)
. For electron
-
rich alkenes, conditions in entry 5 were used for
increasing the
conversion
of alkenes
. For other alkenes, conditions in entry 1 were applied unless otherwise specified.
Table
S
1
.
Reaction
O
ptimization
a
a
Yields determined
by
1
H NMR
analysis
using
dibromomethane as
the
internal standard.
b
With
1
(0.5 mmol)
,
2
(
2
equiv
)
,
3
(1
equiv
)
.
BDD, boron
-
doped diamond
.
Tf, trifluoromethanesulfonyl.
S
5
S4. Cyclic
V
oltammetry
S
tudies
All cyclic voltammetry studies were conducted
in
a nitrogen
-
regulated glovebox
on
EC
Epsilon
(BASi)
. Measurements
were performed in 0.5 M TBAClO
4
in
DME
using a divided three
-
compartment cell.
Mg(OTf)
2
, which bears a redox
-
innocent anion, was used as
the
Mg
2+
source instead of MgCl
2
due to its higher solubility in
DME
. Control experiments
revealed no difference of Mg(OTf)
2
and MgCl
2
in the scan range of
−
3.0
to
0.5 V
v
er
s
us
Zn
2+/0
. Scan rate is 100 mV/s.
Concentration
of
alkyl halides and alkenes
is
0.5 mg/m
L
.
Supporting
e
lectrolyte:
TBAClO
4
was recrystallized
from
EtOAc
for three times and dried under vacuum at 65
°C
overnight.
Solvent:
DME
was first dried overnight with
KOH, and then
reflux
ed
with
sodium and benzophenone under nitrogen
for 5 h.
T
he water
content
was
determined
by a Karl Fischer
t
itrator to be
<5
ppm.
Working electrode:
The working electrode is a glassy carbon electrode
(
3 mm
in
diameter
)
.
It was p
olished with 1.0,
0.3
,
and 0.05 μm
aluminum oxide
,
and then sonicated in distilled water and acetone before air drying and
transferring into the glovebox.
Reference electrode:
The reference electrode consisted of a zinc wire submerged in a saturated solution of Zn(OTf)
2
in
THF. The Zn wire was polished with sandpaper and washed with acetone before transferring into the glovebox.
After each set of
scan, ferrocene was added to re
ference the final potential to ferrocenium/ferrocene redox couple
(Fc
+/0
).
Counter electrode:
The counter electrode is a platinum wire that was
burned
for 30 s with a butane torch
before
transferring into the glovebox
.
Fig
ure
S
2
.
Cyclic voltammetry of
alkene 1,
tert
-
butyl bromide (2)
,
and 1
-
bromo
-
3
-
chloropropane
(3)
.
The onset
potential is
−
2.8,
−
2.4
,
and
−
2.6 V
for
1
,
2
,
and
3
, respectively
,
indicating
tert
-
butyl bromide
under
went
reduction
preferentially
over the others
.
S
6
Fig
ure
S
3
.
Cyclic voltammetry of tertiary
and
primary alkyl bromides with
and without
Mg
2+
.
Mg
2+
does not affect
the redox potential or
peak current.
S
7
Fig
ure
S
4
.
Cyclic voltammetry of
tert
-
butyl bromide
with and without
alkenes.
Current enhancement
wa
s observed
in
both
cases, indicating
that
the intermediates
from
alkyl halide
reduction
can interact with alkenes.
S
8
S5.
V
oltage
P
rofile
M
easurements
All experiments were conducted in a nitrogen
-
regulated glovebox on
a
VMP3 potentiostat (BioLogic).
Electrochemical
dialkylation of alkenes were conducted in a three
-
electrode configuration with Mg counter electrode (CE), graphite
working electrode (WE), an
d Ag wire pseudo
-
reference electrode. The pseudo
-
reference
electrode
is used to isolate
the CE potential changes from those at the WE. The Mg electrode w
as
mechanically ablated within the glovebox,
prior to use, to remove any oxide layer on the surface. The CE and WE were connected to the potentiostat via copper
wire. The experiments were carried out in a 10
-
m
L
round
-
bottom vial equipped with a stir bar and
a screw cap with
pierceable
PTFE
septum. The reaction (1.5 mmol scale) was electrolyzed at a constant current of −2.5 mA (
j
= −0.5
mA/cm
2
) until passing 3.5 F/mol of charge (57 h) at room temperature.
Fig
ure
S
5
.
Electrochemical setup for v
oltage profile
measurements.
(A)
Reaction mixture before electrolysis
.
(B)
Mg
counter electrode after electrolysis in THF.
(C)
Mg counter electrode after electrolysis in DME.
S
9
S
6
. Substrate
S
cope
Fig
ure
S
6
.
Scope of alkenes.
S
10
Fig
ure
S
7
.
Scope of electrophiles.
Boc,
tert
-
butyloxycarbonyl
.
Ts, 4
-
toluenesulfonyl.
S
11
Figure S
8
.
Unsuccessful
substrates
.
The yield
s
w
ere
determined by
1
H NMR analysis using dibromomethane as the
internal standard.
S
12
S
7
.
Characterization
of
P
roducts
5
-
(1
-
Chloro
-
6,6
-
dimethylheptan
-
4
-
yl)benzo[
d
][1,3]dioxole (4)
The reaction was performed on 1.00 mmol scale following
the general procedure
with 2.0
equiv
of primary alkyl
bromide (
Q
= 3.5 F/mol)
. Purification by flash column chromatography (silica gel) afforded the title compound
4
(
224
mg
,
0.792 mg,
79%) as a color
less oil.
1
H NMR
(500 MHz, CDCl
3
,
δ
):
6.70 (
d,
J
= 7.9 Hz, 1H), 6.65 (d,
J
= 1.6 Hz, 1H), 6.60 (dd,
J
= 7.9, 1.6 Hz, 1H), 5.92 (s, 2H),
3.48−3.40 (m, 2H), 2.59−2.51 (m, 1H), 1.75−1.46 (m, 6H), 0.78 (s, 9H).
13
C{
1
H} NMR
(126 MHz, CDCl
3
,
δ
):
147.8, 145.7, 141.0, 121.0, 108.2, 107.8, 100.9, 51.1, 45.3, 42.0, 37.1, 31.4, 30.9,
30.2.
HRMS
(
DART−Orbitrap
,
m
/
z
): [M
−
H]
+
calculated for C
16
H
22
ClO
2
+
: 281.1303; found: 281.1
28
0.
4,4,5,5
-
Tetramethyl
-
2
-
(4,6,6
-
trimethyl
-
1
-
(phenylthio)heptan
-
4
-
yl)
-
1,3,2
-
dioxaborolane
(7)
The reaction was performed on 1.00 mmol scale following
the general procedure
. Purification by flash column
chromatography (silica gel, 1−2%
Et
2
O
in hexanes) afforded the title compound
7
(
278
mg, 0.
73
9 mmol, 7
4
%) as a
white solid.
1
H NMR
(
5
00 MHz, CDCl
3
,
δ
):
7.31 (
d,
J
= 7.6 Hz, 2H), 7.28−7.23 (m, 2H), 7.14 (t,
J
= 7.3 Hz, 1H), 2.92−2.81 (m, 2H),
1.75−1.64 (m, 1H), 1.63−1.46 (m, 3H), 1.30 (apparen
t td,
J
= 12.7, 4.4 Hz, 1H), 1.22−1.15 (m, 13H), 0.95 (s, 3H), 0.93
(s, 9H).
13
C{
1
H} NMR
(1
26
MHz, CDCl
3
,
δ
):
137.2, 128.93, 128.90, 125.7, 83.2, 52.7, 41.1, 34.5, 31.8, 31.7, 25.3, 25.12, 25.08,
22.9. T
he signal of the carbon atom attached to boron was
not observed.
HRMS
(
DART−Orbitrap
,
m
/
z
): [M + H]
+
calculated for C
22
H
38
BO
2
S
+
: 377.2680; found: 377.26
7
0.
(5
-
Methoxy
-
1
-
(1
-
methylcyclohexyl)pentan
-
2
-
yl)benzene (
8
)
The reaction was performed on 1.00 mmol scale following
the general procedure
with 2.0
equiv
of primary alkyl
bromide (
Q
= 3.5 F/mol). Purification by flash column chromatography (silica gel) afforded the title compound
8
(184