Ni-catalyzed Electrochemical Decarboxylative C−−C couplings in Batch andContinuous Flow
Hui Li, † Christopher P. Breen, †‡ Hyowon Seo,‡ Timothy F. Jamison,*‡ Yuan-Qing Fang,*† Matthew M.
Bio,*†† Snapdragon Chemistry, Inc., Cambridge, Massachusetts 02470, United States‡ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

United States

Table of Contents
I.

General Information............................................................................................................ S2

II.

Experimental Procedures and Analytical Data............................................................... S3
Section1. Complete table of reaction optimization.............................................................. S3
Section 2. General procedure for preparation of NHP esters ............................................ S4
Section 3. Reaction setup, general procedure for electrocatalytic arylations in an H-cell. S4
Section 4. Reaction setup, procedure and table of optimization for continuous flow
electrocatalytic arylations...................................................................................................... S6
Section 5. Cyclic voltammetry studies.................................................................................. S8
Section 6. Kinetic studies. ................................................................................................... S9
Section 7. Characterization data for NHP esters ............................................................... S11
Section 8. Characterization data for products. ................................................................. S14

III. NMR Spectra of Compounds .......................................................................................... S21

S1

I.

General Information

General Methods
Reactions were monitored by either offline HPLC or thin layer chromatography (TLC). TLC was
performed using 0.25 mm E. Merck silica plates (60F-254). Visualization was achieved with shortwave
UV light or iodine stain. Flash column chromatography was performed using either SiliaFlash M60 from
SiliCycle, or a Biotage Isolera automated flash chromatography system equipped with SNAP KP-Sil or
Ultra-Sil columns (silica gel, average particle size 50 µm and 25 µm spherical respectively). 1H-NMR
spectra were recorded on either a Varian 500 MHz spectrometer, a Jeol 500 MHz spectrometer, or a
Bruker 400 MHz spectrometer with calibration of spectra to CHCl3 (7.26 ppm). 13C-NMR spectra wererecorded either at 126 MHz on a Varian 500 MHz spectrometer, at 126 MHz on a Jeol 500 MHz
spectrometer, or at 101 MHz on a Bruker 500 MHz spectrometer at ambient temperature with chemical
shifts expressed in ppm using solvent as the internal standard (CDCl3 at 77.16 ppm). 19F-NMR spectra
were recorded on either a Varian 300 MHz at 282 MHz, or a Bruker 500 MHz spectrometer at 376 MHz
spectrometer with chemical shifts reported in ppm and referenced to α,α,α-trifluorotoluene (-63.7 ppm)
added as an internal standard. Chemical shift values (δ) are expressed in ppm downfield relative tointernal standard (tetramethylsilane at 0 ppm). Multiplicities are indicated as s (singlet), d (doublet), t(triplet), q (quartet), p (pentet), m (multiplet), and br s (broad singlet). Coupling constants are reported
in hertz (Hz). Fourier-Transform infrared spectroscopy (FT-IR) data recorded on either a JASCO
FT/IRM4100 Fourier Transform Infrared Spectrometer or an Agilent Cary 630 spectrometer equippedwith an attenuated total response (ATR) accessory. High resolution mass spectra were acquired from
the Mass Spectrometry Laboratory at the Massachusetts Institute of Technology.
Chemicals
Nickel(II) bromide dimethoxyethane adduct (NiBr2dme) was purchased from Strem Chemicals (min97%). 4,4’-Di-tert-butyl-2,2’-dipyridyl (dtbbpy) was purchased from Sigma-Aldrich. Other reagents andsolvents were purchased from Sigma Aldrich, Alfa Aesar, TCI America, Oakwood Chemical, and AK
Scientific. Products were used as received without further purification.
Electrochemical Reactors, Power Supply, Electrode Materials
Electrochemical H-cells were purchased from Pine Research (catalog # RRPG060). A Programmable
DC power supply was purchased from BK Precision (Model 9202). Reticulated vitreous carbon (RVC)
foam was purchased from KR Reynolds (100 ppi) and cut as needed. Stainless steel wires werepurchased from Home Depot.
Continuous-flow electrochemical reactions were performed in a C-Flow LAB 1x1 electrochemical cell(material of cell frame is PEEK), which was purchased from C-Tech Innovation Ltd.. Flow reactors
utilized high-purity PFA tubing (1/8ʺ or 1/16ʺ OD) from Cole-Parmer Instrument Company. Harvard
Apparatus PhD Ultra syringe pumps were used to pump reagents and solutions.

S2

II.

Experimental Procedures and Analytical Data

Section 1.
Table S1. Complete Table of Reaction Optimization

54
6
41
49
48
47
49

Yield (%),
6
11
39
23
20
26
23
14

Yield (%),
7
22
18
21
21
19
24
25

−e

−

−

67
65
74
0
0

9
10
6
0
44

18
15
14
0
38

73

8

14

27
60
0

21
16
0

40
20
<5

Entry Deviation from above

Yield (%), 5

1
2
3
4
5
6
7
8

9
10
11
12
13
14

15
16
17

none
undivided cell
nickel foam cathodeDMF instead of DMA
CH3CN instead of DMA
bpy instead of dtbbpy
dmebpy instead of dtbbpy
Phenanthroline or 2,2’:6’,2”-terpyridine
instead of dtbbpyd
30 mol% NiII/dtbbpy
30 mol% NiII/dtbbpy, Bu4NClO4
30 mol% NiII/dtbbpy, Bu4NPF6
no electricity
no NiBr2glyme
30 mol% NiII/dtbbpy, Bu4NPF6, DIPEA
instead of NEt3
30 mol% NiII/dtbbpy, Bu4NPF6, 60 oC
30 mol% NiII/dtbbpy, Bu4NPF6, 0 oC
ester 4a instead of 4

a Reactions were carried out in 2 mmol scale. b Yield determined by calibrated HPLC assay. c Maximum potential

and current output set at 10 V and 20 mmA, respectively. d Phenanthroline or 2,2’:6’,2”-terpyridine forms
insoluable precipitate with NiBr2glyme in DMAc or DMF. e Not determined

S3

Section 2.

General procedure for preparation of NHP Esters (Procedure A)
O

O
R1
R2

OH
R3

+

HO N

O
EDC HCl, DMAP

R1

CH2Cl2, 0 oC to rt

R2

O
O N

R3
O

O

To a CH2Cl2 solution of alkyl carboxylic acid (1 equiv., ~0.3 M), N-hydroxyphathalimide (1 equiv.) and
DMAP (1.3 equiv.) at 0 oC was added EDCHCl (1.2 equiv.) portionwise. Ice-water bath was removed
and the reaction mixture was stirred at room temperature until the full consumption of starting
carboxylic acid as determined by HPLC or TLC analysis (typically about 2 hours). The reaction was
quenched with 1N HCl and diluted with CH2Cl2. The CH2Cl2 layer was separated, dried over anhydrous
MgSO4 and concentrated in vacuo. The residue then underwent silica gel column chromatography toprovide the corresponding NHP esters.
Section 3. Reaction setup, general procedure for electrocatalytic arylations in an H-cell
Reaction Setup
Figure S1. Overall setup for batch electrochemical coupling performed in an H-cell

Figure S2. Cathode and Anode RVC dimensions

S4

General procedure for electrocatalytic arylations in an H-cell (Procedure B)
R
O
1

R

R2

NHP
R3
8 (1 eq.)+I

X
X = C, N
9 (2 eq.)

30 mol% NiBr2 glyme
30 mol% dtbbpy, NEt3 (6 eq.)
Bu 4NPF6 (2 eq.), DMA, rt
RVC (+)/( −), H-Cell
10 V/20 mA, 5-6 h

R
R1
R2

X
R

3

10

NiBr2dme (0.6 mmol) and dtbbpy (0.6 mmol) were dissolved in N-N-dimethylacetamide (DMA) (6 mL)
and stirred at 60 °C until a green homogeneous solution was obtained (generally within 1 h). The
solution was then cooled to room temperature.
To the cathode chamber of an H-cell was added NHP ester 8 (2 mmol)1, aryl halide 9 (4 mmol),
Bu4NPF6 (1.55 g, 4 mmol), the above freshly prepared NiBr2dme/dtbbpy solution and DMA (~11 mL, so
that the total volume of solution in cathode side is about 18 mL).
To the anode chamber of an H-cell was added triethylamine (1.67 mL, 12 mmol), Bu4NPF6 (1.55 g, 4mmol) and DMA (~16 mL, so that the total volume of solution in anode side is about 18 mL).
Part of the RVC cathode and anode were submerged into the reaction mixtures (Figure S3-A).
Generally about 4.5-5 cm3 of cathode RVC foam was submerged.2 The cathode solution was purged
with nitrogen for about 5 min. The reaction mixture was then electrolyzed at 10 V/20 mA (maximum
potential and current, respectively) at room temperature until full consumption of starting NHP ester 8
as determined by HPLC analysis. Color changes were observed for both cathode and anode mixtures,
which turned deep-brown at the end of reaction (Figure S3-B).
The cathodic reaction mixture was transferred into a separatory funnel and diluted with ethyl acetate(40 mL). The mixture was washed with brine/H2O (v/v = 1:1, 15 mL) three times. The ethyl acetate layer
was separated, dried over anhydrous MgSO4, and concentrated in vacuo. The residue then underwent
silica gel column chromatography to provide the corresponding arylated products.
Figure S3. Close-up of H-cell

1
2

All reactions were performed on 2-mmol scale.
It is important to make sure that the stainless steel wire used to hang the RVC not be in contact with reaction mixture.

S5

Section 4. Reaction setup, procedure and table of optimization for continuous-flow
electro-catalytic arylations
Reaction setup
Figure S4. Overall setup for reaction performed in a continuous-flow mode

As shown in Figure S5-A, RVC carbon foams (100 ppi) were attached to the anode and cathodegraphite plates of C-flow® cell frames so as to increase the surface area of both electrodes. Figure S5-B
and S5-C show the dimension of the carbon foam, which is ~1 cm3. The internal wet volume of cathodeor anode cell frame is about 0.5 mL.
Figure S5. Close-up of a cell frame: A (cell frame attached with RVC), B+C (dimensions of RVC)

General procedure for flow experiments (Procedure C)
Preparation of cathode solution: NHP ester 4 (2 mmol), iodobenzene (4 mmol), Bu4NBP6 (1.55 g, 4mmol), freshly prepared NiBr2dme/dtbbpy (0.6 mmol) solution in DMA (see Procedure B for
preparation), then diluted with DMA to 20 mL. The solution was then loaded into a 24-mL syringe.

S6

Preparation of anode solution: triethylamine (1.67 mL, 12 mmol), Bu4NBP6 (1.55 g, 4 mmol), thendiluted with DMA to 20 mL. The solution was then loaded into a 24-mL syringe.
The electrochemical flow cell shown in Figure S4 was conditioned by having 10 mL of Bu4NPF6/DMA(0.2 M) flowed through it so as to wet electrodes and nafion membrane. After connecting the flow cellwith the power supply, the cathode and anode solutions were delivered by a Harvard syringe pump at
the same flow rate into the flow cell. Reaction streams flowing out of the cathode and anode cell frames
were collected in scintillation vials. When a flow condition has changed, we waited for about 5
residence time before collecting a sample for HPLC assay so that the sample collected isrepresentative of the steady state reaction.
Table of optimization for continuous-flow electro-catalytic arylations

Table S2. Flow rate and current density studiesa
flow rateyield (%)djtRmass balance selectivity
entry
3
b
c
(mA/cm ) (µL/min) (min)(%)(5 : 6)
5
6
7
1
38.1
100
5.0
44
39
8
91
1.1
2
38.1
110
4.5
52
34
8
94
1.5
3
38.1
130
3.8
54
33
8
95
1.6
4
38.1
140
3.6
52
29
7
88
1.8
5
38.1
160
3.1
49
22
9
80
2.2
6
29.2
83
6.0
47
32
7
86
1.5
7
29.2
100
5.0
58
23
8
89
2.5
8
29.2
110
4.2
61
19
8
88
3.2
9
29.2
120
3.9
62
17
10
89
3.7
10
29.2
130
3.8
57
14
10
81
4.1
11
13.7
50
10
70
12
9
91
5.8
12
13.7
60
8.3
81
7
8
96
11.6
13
13.7
70
7.1
74
6
10
90
12.3
a Cathode stream: 4 (0.1 M), PhI (2 eq.) NiBr2dme/dtbbpy (30 mol%), Bu4NPF6 (0.2 M); anode stream:
NEt3 (6 eq.), Bu4NPF6 (0.2 M). b j = current density, mA per cubic centimeter of RVC carbon foam (100S7ppi). c Internal wet volume of anode or cathode flow cell is 0.5 mL. d Yield determined by calibrated
HPLC assay.
Representative HPLC chromatogram of reaction mixture in flow (Table S2, entry 12)

Section 5. Cyclic voltammetry studies
Cyclic voltammetry studies were conducted with an Autolab PGSTAT101 potentiostat/galvanostat asshown in Figure S6. The electrochemical cell (catalog # AKCELL1) and electrodes were purchasedfrom Pine Research. A glassy carbon disc (catalog # AFE1XFP030GCR) was used as the working
electrode and Pt wire (catalog # AFCTR5) as the counter electrode. Redox potentials are reported
versus a Ag/AgCl reference electrode (catalog # RREF0021). To the electrochemical cell was added thecompound of interest (0.05 mmol), Bu4NClO4 (1.71 g, 5 mmol) and CH3CN (50 mL). The mixture wassparged with nitrogen for 5 min before cyclic voltammetry measurements.
Figure S6. Cyclic voltammetry study with Autolab PGSTAT101

Figure S7. CV of NHP ester 4

S8

Figure S8. CV of iodobenzene

Figure S9. CV of NiBr2/dtbbpy complex

Section 6. Reaction kinetics study
Ph
4

O
NHP
+

I Ph (2 eq.)

20 mol% NiBr2 dme
20 mol% dtbbpy, NEt3 (6 eq.)
Bu 4NBr (2 eq.), DMA, rt
RVC (+)/( −), H-Cell
10 V 20 mA c, 3-6.5 h

S9

Ph

Ph
Ph
5

6

+
Ph

O
7
OH

Ph

Kinetic study was performed on the reaction between NHP ester 4 and iodobenzene. To the cathodechamber of an H-cell was added NHP ester 4 (2 mmol), iodobenzene (4 mmol), Bu4NBr (1.29 g, 4mmol), freshly prepared NiBr2dme/dtbbpy solution (0.4 mmol, see Procedure B for preparation) andDMA (~11 mL, so that the total volume of solution in cathode side is about 18 mL). To the anodechamber of an H-cell was added triethylamine (1.67 mL, 12 mmol), Bu4NBr (1.29 g, 4 mmol) and DMA(~16 mL, so that the total volume of solution in anode side is about 18 mL). The cathode solution was
purged with nitrogen for about 5 min. The reaction mixture was then electrolyzed at 10 V/20 mA(maximum potential and current, respectively) at room temperature.
Sampling was performed by accurately withdrawing 50 µL of cathode reaction mixture and diluted with
950 µL of CH3CN (20x dilution), which was followed by calibrated HPLC assay. Table S3 and Figure
S10 shows the yields of compounds 5, 6, 7, as well as the amount of charge and electron passed
through the system over time.

entry

1
2
3
4
5
6
7
8

Table S3. Reaction yields, amount of charge and electron over timeyield (%)
reactionchargeelectrontime (h)passed (C) passed (mmol)
5
6
7
0.67
1
0
0.8
43.2
0.45
1.17
3
0
1
75.6
0.79
2.00
13
0
1.5
129.6
1.35
2.67
28
0
1.5
173.4
1.80
3.33
39
3.5
12.6
219.0
2.28
4.00
48
8
19
264.6
2.75
4.50
51
9
21
298.8
3.11
5.00
52
10
21
333.0
3.46

Figure S10. Kinetic profile of electro-catalytic coupling between 4 and iodobenzene

S10Section 7. Characterization data for NHP esters

Procedure A was followed with hydrocinnamic acid (20 mmol) to yield 4.9607 g (84 %) of product as awhite solid after flash chromatography (20% EtOAc/hexanes).
1H NMR (500 MHz, Chloroform-d) δ 7.88 (dd, J = 5.3, 3.2 Hz, 2H), 7.78 (dd, J = 5.6, 3.1 Hz, 2H), 7.33 (t,J = 7.6 Hz, 2H), 7.28 – 7.22 (m, 3H), 3.10 (t, J = 7.8 Hz, 2H), 2.98 (t, J = 7.8 Hz, 2H).
13C NMR (101 MHz, Chloroform-d) δ 169.01, 162.02, 139.31, 134.89, 129.04, 128.85, 128.43, 126.84,

124.11, 32.85, 30.68.
This data is in agreement with what has been previously reported for this compound.3

Procedure A was followed using levulinic acid (10 mmol) to yield 1.6313 g (62 %) of product as acolorless solid after flash chromatography (40 % EtOAc/hexanes).
1H NMR (500 MHz, Chloroform-d) δ 7.88 (dd, J = 5.4, 3.2 Hz, 2H), 7.79 (dd, J = 5.5, 3.1 Hz, 2H), 3.00 –2.89 (m, 4H), 2.23 (s, 3H).

13C NMR (126 MHz, Chloroform-d) δ 205.10, 169.30, 161.91, 134.92, 128.98, 124.14, 37.78, 29.83,

25.23.
IR neat (cm-1) 1740, 1700, 1604, 1358, 1331, 1251, 1024, 1014, 877, 750.
HRMS: 262.0710 m/z [M+H]+ calc’d for C13H11NO5, 262.0701 m/z observed.

Procedure A was followed with 4-pentynoic acid (10 mmol) to yield 2.2863 g (94 %) of product as a
3

Lv, Y.; Sun, K.; Pu, W.; Mao, S.; Li, G.; Niu, J.; Chen, Q.; Wang, T. RCS Adv. 2016, 6, 93486-93490

S11

colorless solid after flash chromatography (20 % EtOAc/hexanes).
1H NMR (500 MHz, Chloroform-d) δ 7.89 (dd, J = 5.4, 3.2 Hz, 2H), 7.80 (dd, J = 5.5, 3.0 Hz, 2H), 2.95 (t,J = 7.5 Hz, 2H), 2.66 (td, J = 7.5, 2.6 Hz, 2H), 2.07 (t, J = 2.6 Hz, 1H).
13C NMR (126 MHz, Chloroform-d) δ 168.09, 161.87, 134.97, 128.94, 124.15, 81.04, 70.18, 30.47,

14.29.
IR neat (cm-1): 3278, 1784, 1738, 1467, 1413, 1373, 1356, 1184, 1132, 1078, 1037, 961, 864, 787, 692.
HRMS: 244.0604 m/z [M+H]+ calc’d for C13H9NO4, 244.0599 m/z observed.

Procedure A was followed with tetrahydro-2-furoic acid (10 mmol) to yield 1.7455 g (67 %) of product asa white solid after flash chromatography (20 % EtOAc/hexanes).
1H NMR (500 MHz, Chloroform-d) δ 7.89 (dd, J = 5.4, 3.1 Hz, 2H), 7.80 (dd, J = 5.5, 3.1 Hz, 2H), 4.88

(dd, J = 8.6, 4.9 Hz, 1H), 4.10 (q, J = 7.5, 7.1 Hz, 1H), 4.01 (q, J = 7.5, 7.1 Hz, 1H), 2.50 – 2.34 (m, 2H),
2.07 (dtd, J = 41.4, 13.5, 13.0, 6.8 Hz, 2H).
13C NMR (101 MHz, Chloroform-d) δ 169.91, 161.85, 134.95, 129.03, 124.16, 75.09, 70.00, 31.03,

25.23.
The 1H and 13C NMR spectra are in agreement with those reported in the literature.4

Procedure A was followed with cyclobutanecarboxylic acid (10 mmol) to yield 1.9012 g (78 %) of
product as a white solid after flash chromatography (15-25% EtOAc/hexanes).
1H NMR (500 MHz, Chloroform-d) δ 7.89 (dd, J = 5.4, 3.1 Hz, 2H), 7.79 (dd, J = 5.5, 3.1 Hz, 2H), 3.52

(p, J = 8.4 Hz, 1H), 2.56 – 2.47 (m, 2H), 2.41 (dtd, J = 12.9, 8.7, 4.6 Hz, 2H), 2.17 – 2.00 (m, 2H).

4

Cornella, J.; Edwards, J.T.; Qin, T.; Kawamura, S.; Wang, J.; Pan, C.; Gianatassio, R.; Schmidt, M.; Eastgate, M. D.; Baran,
P.S. J. Am Chem. Soc. 2016, 138, 2174-2177

S12

13C NMR (101 MHz, Chloroform-d) δ 171.53, 162.21, 134.84, 129.12, 124.05, 35.17, 25.52, 18.86.

The 1H and 13C NMR spectra are in agreement with those reported in the literature.4

Procedure A was followed with 1-adamantanecarboxylic acid (10 mmol) to yield 3.0681 g (94 %) of
product as a white solid after flash chromatography (10-25 % EtOAc/hexanes).
1H NMR (500 MHz, Chloroform-d) δ 7.88 (dd, J = 5.4, 3.1 Hz, 2H), 7.78 (dd, J = 5.5, 3.1 Hz, 2H), 2.16 –2.13 (m, 6H), 2.12 – 2.08 (m, 3H), 1.79 – 1.76 (m, 6H).
13C NMR (126 MHz, Chloroform-d) δ 173.38, 162.28, 134.75, 129.19, 123.96, 40.62, 38.56, 36.31,

27.75.
This data is consistent with what has been previously reported for this compound.5

Procedure A was followed with linoleic acid (15.0 mmol) to yield 4.0474 g (63 %) of product as acolorless oil after flash chromatography (5 % EtOAc/hexanes).
1H NMR (500 MHz, Chloroform-d) δ 7.88 (dd, J = 5.4, 3.1 Hz, 2H), 7.78 (dd, J = 5.5, 3.1 Hz, 2H), 5.42 –5.29 (m, 4H), 2.77 (t, J = 6.6 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 2.08 – 2.02 (m, 4H), 1.78 (p, J = 7.5 Hz,
2H), 1.48 – 1.41 (m, 2H), 1.39 – 1.26 (m, 13H), 0.88 (t, J = 6.9 Hz, 3H).
13C NMR (101 MHz, Chloroform-d) δ 169.76, 162.15, 134.86, 130.37, 130.16, 129.11, 128.22, 128.06,

124.08, 31.67, 31.14, 29.71, 29.50, 29.18, 28.95, 27.36, 27.33, 25.79, 24.81, 22.72, 14.22.
IR neat (cm-1): 2918, 2851, 1826, 1789, 1739, 1610, 1466, 1404, 1374, 1281, 1249, 1217, 1185, 1141,
1069, 1048, 1020, 984, 861, 878, 854, 791, 721, 692
HRMS: 425.2566 m/z [M+H]+ calc’d for C26H36NO4, 425.2519 m/z observed.

5

Pratsch, G.; Lackner, G.L.; Overman, L.E. J. Org. Chem. 2015, 80, 6025-6036

S13

The procedure for making this compound was adapted from Weix and coworkers.6 To an oven dried flask
was added Boc-L-glutamic acid 1-tert-butyl ester (5.0 mmol, 1.00 eq.) and dissolved in 25 mL (0.2 M) of
THF with magnetic stirring. N-hydroxyphthalimide (8.3 mmol, 1.66 eq.) was then added to the flask,
followed by N,N’-diisopropylcarbodiimide (7.5 mmol, 1.50 eq.), and finally 4-(dimethylamino)pyridine(0.25 mmol, 0.0500 eq.). The reaction mixture was stirred at room temperature for 4 hours after which thereaction was judged to be complete by HPLC analysis. The heterogeneous reaction mixture was thenfiltered and condensed under negative pressure. The crude isolate was then purified by flash
chromatography using EtOAc/hexanes to yield 1.4800 g (66 %) of the title compound as a white solid.
1H NMR (500 MHz, Chloroform-d) δ 7.88 (dd, J = 5.7, 3.0 Hz, 2H), 7.79 (dd, J = 5.4, 2.5 Hz, 2H), 5.19

(d, J = 7.0 Hz, 1H), 4.28 (d, J = 7.2 Hz, 1H), 2.85 – 2.67 (m, 2H), 2.37 – 2.25 (m, 1H), 2.11 – 2.01 (m,1H), 1.47 (d, J = 16.3 Hz, 18H).
13C NMR (101 MHz, Chloroform-d) δ 170.94, 169.11, 161.95, 155.56, 134.92, 129.05, 124.13, 82.80,

80.17, 53.27, 28.45, 28.15, 27.56.
This data is consistent with what has been previously reported for this compound.6
Section 8. Characterization data for coupling products

Ph

Ph
10a

Procedure B was followed with 1,3-dioxoisoindolin-2-yl 4-phenylbutanoate (618 mg, 2 mmol) andiodobenzene (450 µL, 4 mmol). Purification was performed by silica gel column chromatography (100 %hexane) to give 263 mg of product as a colorless oil, with an isolated yield of 67%.
1H NMR (400 MHz, Chloroform-d) δ 7.46 – 7.13 (m, 9H), 2.72 (t, J = 7.8 Hz, 4H), 2.12 – 1.93 (m, 2H).

13C NMR (126 MHz, Chloroform-d) δ 142.38, 128.55, 128.42, 125.85, 35.56, 33.08.

The 1H and 13C NMR spectra are in agreement with those reported in the literature.6

Procedure B was followed with 1,3-dioxoisoindolin-2-yl 1-tosylpiperidine-4-carboxylate (428.5 mg, 1mmol) and iodobenzene (225 µL, 2 mmol). Purification was performed by silica gel column
chromatography (10% EtOAc/hexane) to give 204 mg of product as a colorless solid, with an isolated
yield of 63%.

6

Huihui, K. M. M.; Caputo, J. A.; Melchor, Z.; Olivares, A. M.; Spiewak, A. M.; Johnson, K. A.; DiBenedetto, T. A.; Kim, S.;
Ackerman, L. K. G.; Weix, D. J. J. Am. Chem. Soc. 2016, 138, 5016−5019

S14

1H NMR (500 MHz, Chloroform-d) δ 7.68 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 7.29 (t, J = 7.5 Hz,

2H), 7.25 – 7.18 (m, 1H), 7.17 – 7.10 (m, 2H), 3.93 (d, J = 11.7 Hz, 2H), 2.45 (s, 3H), 2.44 – 2.30 (m, 3H),
1.95 – 1.77 (m, 4H).
13C NMR (126 MHz, Chloroform-d) δ 144.89, 143.47, 133.12, 129.61, 128.57, 127.76, 126.67, 126.57,

46.86, 41.83, 32.53, 21.53.
The 1H and 13C NMR spectra are in agreement with those reported in the literature.7

Procedure B was followed with 1,3-dioxoisoindolin-2-yl 1-Boc-piperidine-4-carboxylate (745 mg, 2 mmol)and iodobenzene (450 µL, 4 mmol). Purification was performed by silica gel column chromatography(3-5% EtOAc/hexane) to give 318 mg of product as a colorless oil, with an isolated yield of 65%.
1H NMR (400 MHz, Chloroform-d) δ 7.35 – 7.27 (m, 2H), 7.25 – 7.16 (m, 3H), 4.25 (s, 2H), 2.80 (t, J =13.0 Hz, 2H), 2.70 – 2.54 (m, 1H), 1.82 (d, J = 13.1 Hz, 2H), 1.63 (dd, J = 12.5, 4.1 Hz, 2H), 1.49 (d, J =1.7 Hz, 9H).
13C NMR (126 MHz, Chloroform-d) δ 154.88, 145.81, 128.53, 126.79, 126.36, 79.41, 44.43, 42.75, 33.23,

28.53.
The 1H and 13C NMR spectra are in agreement with those reported in the literature.7

Procedure B was followed with 1,3-dioxoisoindolin-2-yl cyclohexanecarboxylate (547 mg, 2 mmol) andiodobenzene (450 µL, 4 mmol). Purification was performed by silica gel column chromatography(hexane) to give 198 mg of product as a colorless oil, with an isolated yield of 62%.
1H NMR (500 MHz, Chloroform-d) δ 7.39 – 7.33 (m, 2H), 7.31 – 7.27 (m, 2H), 7.25 (m, 1H), 2.57 (d, J =3.5 Hz, 1H), 2.01 – 1.87 (m, 4H), 1.83 (ddd, J = 12.8, 3.1, 1.5 Hz, 1H), 1.57 – 1.42 (m, 4H), 1.34 (dd, J =12.6, 3.6 Hz, 1H).
13C NMR (126 MHz, Chloroform-d) δ 148.12, 128.31, 126.86, 125.81, 44.68, 34.54, 27.00, 26.26.

The 1H and 13C NMR spectra are in agreement with those reported in the literature.7

Toriyama, F.; Cornella, J.; Wimmer, L.; Chen, T.-G.; Dixon, D. D.; Creech, G.; Baran, P. S. J. Am. Chem. Soc. 2016, 138,
11132−11135

7

S15

Procedure B was followed with 1,3-dioxoisoindolin-2-yl cyclopropanecarboxylate (462 mg, 2 mmol) andiodobenzene (450 µL, 4 mmol). Purification was performed by silica gel column chromatography(hexane) to give 97 mg of product as a colorless oil, with an isolated yield of 41%.
1H NMR (500 MHz, Chloroform-d) δ 7.31 (t, J = 7.6 Hz, 2H), 7.20 (td, J = 7.5, 1.0 Hz, 1H), 7.16 – 7.10 (m,2H), 1.95 (tt, J = 8.4, 5.1 Hz, 1H), 1.01 (dd, J = 8.4, 2.1 Hz, 2H), 0.86 – 0.66 (m, 2H).
13C NMR (126 MHz, Chloroform-d) δ 144.07, 128.38, 125.77, 125.47, 15.51, 9.31.

The 1H and 13C NMR spectra are in agreement with those reported in the literature.8

Procedure B was followed with 1,3-dioxoisoindolin-2-yl cyclopropanecarboxylate (651 mg, 2 mmol) andiodobenzene (450 µL, 4 mmol). Purification was performed by silica gel column chromatography (100 %hexanes) to give 97 mg of product as a colorless solid, with an isolated yield of 52%.
1H NMR (500 MHz, Chloroform-d) δ 7.38 (d, J = 7.5 Hz, 2H), 7.33 (t, J = 7.8 Hz, 2H), 7.18 (t, J = 7.2 Hz,

1H), 2.11 (m, 3H), 1.93 (d, J = 3.0 Hz, 6H), 1.84 – 1.74 (m, 6H)
13C NMR (126 MHz, Chloroform-d) δ 151.5, 128.2, 125.6, 125.0, 43.3, 37.0, 36.3, 29.1

The 1H and 13C NMR spectra are in agreement with those reported in the literature.7

Procedure B was followed with 1,3-dioxoisoindolin-2-yl 3-phenylpropanoate (590 mg, 2.0 mmol) and
1-iodonaphthalene (584 µL, 4 mmol). Purification was performed by Biotage Ultra-Sil 50 g column (100%pentane) to give 219 mg of product as a colorless oil, with an isolated yield of 47 %.
1H NMR (500 MHz, Chloroform-d) δ 8.12 (dd, J = 8.5, 1.0 Hz, 1H), 7.89 (dd, J = 8.0, 1.5 Hz, 1H), 7.75 (d,J = 8.2 Hz, 1H), 7.55 (ddd, J = 8.4, 6.8, 1.6 Hz, 1H), 7.50 (ddd, J = 8.0, 6.8, 1.3 Hz, 1H), 7.40 (dd, J = 8.2,
7.0 Hz, 1H), 7.36 – 7.30 (m, 3H), 7.29 – 7.23 (m, 3H), 3.42 – 3.37 (m, 2H), 3.10 – 3.05 (m, 2H).
13C NMR (126 MHz, Chloroform-d) δ 142.11, 137.90, 134.01, 131.88, 128.98, 128.55, 126.89, 126.14,

126.11, 126.00, 125.68, 125.60, 123.76, 37.22, 35.25.
The 1H and 13C NMR spectra are in agreement with those reported in the literature.9

89Zhou, Y.; Uyeda, C. Angew. Chem. Int. Ed. 2016, 55, 3171-3175
Shen, Z. L.; Goh, K. K. K.; Yang, Y. S.; Lai, Y. C.; Wong, C. H. A.; Cheong, H. L.; Loh, T. P. Angew. Chem. Int. Ed. 2011,
50, 511-514

S16

Procedure B was followed with 1,3-dioxoisoindolin-2-yl 3-phenylpropanoate (590 mg, 2 mmol) and
3-chloro-4-fluoroiodobenzene (510 µL, 4 mmol). Purification was performed by Biotage Ultra-Sil 50 gcolumn (100% penatne) to give 245 mg of product as a clear oil, with an isolated yield of 50 %.
1H NMR (500 MHz, Chloroform-d) δ 7.31 (t, J = 7.4 Hz, 2H), 7.25 – 7.19 (m, 2H), 7.17 (d, J = 7.9 Hz, 2H),

7.04 (t, J = 8.6 Hz, 1H), 7.02 – 6.98 (m, 1H), 2.90 (s, 4H).
13C NMR (126 MHz, Chloroform-d) δ 156.65 (d, J = 246.4 Hz), 141.04, 138.72 (d, J = 4.1 Hz), 130.52,

128.55 (d, J = 2.0 Hz), 128.20 (d, J = 7.0 Hz), 126.28, 120.57 (d, J = 17.6 Hz), 116.37 (d, J = 20.8 Hz),37.81 (d, J = 1.5 Hz), 36.96.
19F NMR (282 MHz, Chloroform-d) δ -120.77 – -120.98 (m).

IR Neat (cm-1): 3028, 2928, 2859, 1602, 1497, 1453, 1406, 1245, 1059, 874, 812, 749, 696.
EI LRMS: 234.1 m/z [M]+ calc’d for C14H12ClF, 234.1 m/z observed.

Procedure B was followed with 1,3-dioxoisoindolin-2-yl 3-phenylpropanoate (590 mg, 2 mmol) and
3-iodopyridine (820 mg, 4 mmol). Purification was performed by silica gel column chromatography (40%EtOAc/hexane) to give 190 mg of product as a colorless oil, with an isolated yield of 52 %.
1H NMR (400 MHz, Chloroform-d) δ 8.46 (dt, J = 6.4, 1.9 Hz, 2H), 7.50 – 7.39 (m, 1H), 7.30 (t, J = 7.5 Hz,

2H), 7.26 – 7.09 (m, 4H), 2.95 (s, 4H)
13C NMR (126 MHz, Chloroform-d) δ 150.11, 147.63, 147.60, 140.93, 136.93, 136.07, 128.59, 128.58,

126.32, 123.39, 123.34, 37.59, 35.07
The 1H and 13C NMR spectra are in agreement with those reported in the literature.7

Procedure B was followed with 1,3-dioxoisoindolin-2-yl cyclobutanecarboxylate (491 mg, 2.0 mmol) and
3-iodopyridine (820 mg, 4.0 mmol). Purification was performed by Biotage Ultra-Sil 25 g column (10 –20% ethyl acetate/hexanes) to give 152 mg of product as a clear liquid, with 57 % isolated yield.
1H NMR (500 MHz, Chloroform-d) δ 8.45 (s, 1H), 8.41 (d, J = 4.6 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.20

(dd, J = 7.8, 4.8 Hz, 1H), 3.54 (p, J = 8.6 Hz, 1H), 2.36 (q, J = 8.5 Hz, 2H), 2.19 – 2.09 (m, 2H), 2.04 (dt,
J = 18.4, 9.6 Hz, 1H), 1.88 (q, J = 8.8 Hz, 1H).
S17

13C NMR (126 MHz, Chloroform-d) δ 148.46, 147.26, 141.13, 133.74, 123.22, 37.86, 29.57, 18.56.
IR Neat (cm-1): 2967, 2938, 2864, 1573, 1477, 1420, 1244, 1025, 995, 805, 711.

HRMS: 134.0964 m/z [M+H]+ calc’d for C9H11N, 134.0964 m/z observed.

Procedure B was followed with 1,3-dioxoisoindolin-2-yl tetrahydrofuran-2-carboxylate (522.4 mg, 2mmol) and 4-iodobenzotrifluoride (1.09 g, 4 mmol). Purification was performed by Biotage Ultra-Sil 25 gcolumn (3 – 15% ethyl acetate/hexanes) to give 226 mg of product as a clear oil, with an isolated yieldof 52 %.
1H NMR (400 MHz, Chloroform-d) δ 7.58 (d, J = 8.1 Hz, 2H), 7.48 – 7.41 (m, 2H), 4.95 (t, J = 7.2 Hz, 1H),

4.11 (dt, J = 8.4, 6.8 Hz, 1H), 3.96 (dt, J = 8.3, 6.9 Hz, 1H), 2.37 (dq, J = 12.2, 6.7 Hz, 1H), 2.08 – 1.96 (m,2H), 1.77 (dq, J = 12.3, 7.7 Hz, 1H).
13C NMR (101 MHz, Chloroform-d) δ 197.1, 147.7, 125.7, 125.2 (q, J = 3.9 Hz) 68.9, 34.7, 25.9.
19F NMR (376 MHz, Chloroform-d) δ -63.4.

IR Neat (cm-1): 2872, 1620, 1417, 1324, 1162, 1121, 1066, 1017, 823, 837.
HRMS: 217.0835 m/z [M+H]+ calc’d for C11H11F3O, 217.0846 m/z observed.

Procedure B was followed with 1,3-dioxoisoindolin-2-yl cyclohexanecarboxylate (547 mg, 2 mmol) and
4-iodoanisole (936 mg, 4 mmol). Purification was performed by silica gel column chromatography (3-4%
EtOAc/hexane) to give 152 mg of product as a colorless solid, with an isolated yield of 40%.
1H NMR (500 MHz, Chloroform-d) δ 7.21 – 7.09 (m, 2H), 6.85 (d, J = 8.7 Hz, 2H), 3.80 (s, 3H), 2.54 – 2.39(m, 1H), 1.94 – 1.79 (m, 4H), 1.79 – 1.70 (m, 1H), 1.47 – 1.34 (m, 4H), 1.27 (tt, J = 12.8, 3.4 Hz, 1H).
13C NMR (126 MHz, Chloroform-d) δ 157.78, 140.50, 127.75, 127.74, 113.78, 55.37, 43.83, 34.87, 27.11,

26.33.
The 1H and 13C NMR spectra are in agreement with those reported in the literature.10

10Liu, D.; Li, Y.; Liu, C.; Lei, A.; Qi, X.; Lan, Y. Org. Lett. 2016, 17, 6456-6459

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Procedure B was followed with 1,3-dioxoisoindolin-2-yl tetrahydrofuran-2-carboxylate (522.4 mg, 2mmol) and methyl 4-iodobenzoate (1.05 g, 4 mmol). Purification was performed by Biotage Ultra-Sil 25
g column (3 – 15% ethyl acetate/hexanes) to give 242 mg of product as a colorless solid, with anisolated yield of 59 %.
1H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 4.94 (t, J = 7.2 Hz,

1H), 4.11 (dt, J = 8.3, 6.8 Hz, 1H), 3.95 (dt, J = 8.3, 7.0 Hz, 1H), 3.90 (s, 3H), 2.36 (dq, J = 12.3, 6.7 Hz,
1H), 2.07 – 1.95 (m, 2H), 1.77 (dq, J = 12.2, 7.6 Hz, 1H).
13C NMR (101 MHz, Chloroform-d) δ 167.0, 148.9, 129.6, 128.9, 125.4, 80.2, 68.8, 52.0, 34.7, 25.9.

IR Neat (cm-1): 2953, 2869, 1718, 1811, 1576, 1435, 1414, 1377, 1275, 1175, 1109, 1062, 1018, 965,
922, 856, 765, 706.
HRMS: 207.1016 m/z [M+H]+ calc’d for C12H14O3, 207.1026 m/z observed.

Procedure B was followed with 1,3-dioxoisoindolin-2-yl 4-oxopentanoate (522 mg, 2 mmol) andiodobenzene (450 µL, 4 mmol). Purification was performed by silica gel column chromatography (5%EtOAc/hexane) to give 225 mg of product as a colorless solid, with an isolated yield of 76%.
1H NMR (500 MHz, Chloroform-d) δ 7.29 (s, 2H), 7.23 – 7.15 (m, 3H), 2.90 (d, J = 7.8 Hz, 2H), 2.77 (d, J= 8.1 Hz, 2H), 2.14 (s, 3H).
13C NMR (126 MHz, Chloroform-d) δ 207.92, 141.05, 128.34, 126.16, 45.20, 30.11, 29.79.

The 1H and 13C NMR spectra are in agreement with those reported in the literature.11

Procedure B was followed with 1,3-dioxoisoindolin-2-yl (9Z,12Z)-octadeca-9,12-dienoate (1.374 g, 2mmol) and 2-iodobenzonitirle (916 mg, 4 mmol). Purification was performed by Biotage Ultra-Sil 25 gcolumn (3 – 15% EtOAc/hex) to give 235 mg of product as a colorless oil, with a yield of 35 %.
11

Moteki, S.; Usui, A.; Zhang, T.; Solorio Alvarado, C.; Maruoka, K. Angew. Chem. Int. Ed. 2013, 52, 8657-8660

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1H NMR (400 MHz, Chloroform-d) δ 7.60 (dd, J = 7.7, 1.3 Hz, 1H), 7.50 (td, J = 7.7, 1.5 Hz, 1H), 7.33 –7.24 (m, 2H), 5.43 – 5.27 (m, 4H), 2.89 – 2.81 (m, 2H), 2.81 – 2.73 (m, 2H), 2.05 (q, J = 6.9 Hz, 4H), 1.76
– 1.62 (m, 2H), 1.45 – 1.23 (m, 14H), 0.94 – 0.83 (m, 3H).
13C NMR (101 MHz, CDCl3) δ 146.8, 132.7, 132.6, 130.2, 130.1, 129.4, 128.0, 127.9, 126.3, 118.2, 112.3,

34.6, 31.5, 30.9, 29.6, 29.3, 29.3, 29.2, 29.2, 27.2, 25.6, 22.6, 14.1.
IR Neat (cm-1): 3011, 2927, 2857, 2252, 2141, 2100, 1998, 1958, 1600, 1486, 1465, 761, 725.
HRMS: 338.2842 m/z [M+H]+ calc’d for C24H35N, 338.2841 m/z observed.

ProcedureB
wasfollowedwith1-(tert-butyl)
5-(1,3-dioxoisoindolin-2-yl)(tert-butoxycarbonyl)-L-glutamate (897 mg, 2 mmol) and 4-iodophenylboronic acid pinacol ester (1.32 g,
4 mmol). Purification was performed by Biotage Ultra-Sil 25 g column (3 – 10% EtOAc/hexane) to give
360 mg of product as a colorless solid, with an isolated yield of 39%.
1H NMR (400 MHz, Chloroform-d) δ 7.73 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 5.06 (d, J = 8.3 Hz,

0.5H), 4.24 (d, J = 7.2 Hz, 0.5H), 2.67 (qt, J = 13.7, 7.3 Hz, 2H), 2.13 – 2.04 (m, 1H), 1.95 – 1.82 (m, 1H),
1.47 (s, 9H), 1.45 (s, 9H), 1.33 (s, 12H).
13C NMR (101 MHz, CDCl3) δ 171.7, 155.3, 144.6, 135.0, 127.8, 83.7, 81.9, 79.7, 53.9, 34.7, 31.8, 28.3,

28.0, 24.8.
IR (neat, cm-1) 2978, 2935, 2873, 1716, 1612, 1510, 1454, 1361, 1320, 1174, 1149, 1147, 1090, 1060,
1023, 963, 859, 827, 738, 659.
HRMS: 461.3058 m/z [M+H]+ calc’d for C25H40BNO6, 461.3065 m/z observed.

Procedure B was followed with 1,3-dioxoisoindolin-2-yl 2-cyclopropylacetate (490 mg, 2 mmol) andiodobenzene (450 µL, 4 mmol). Purification was performed by silica gel column chromatography(hexane) to give 121 mg of product as a colorless solid, with an isolated yield of 46%.
1H NMR (500 MHz, Chloroform-d) δ 7.32 (dd, J = 8.2, 6.9 Hz, 2H), 7.23 (d, J = 7.3 Hz, 3H), 5.91 (ddtd, J= 16.9, 10.2, 6.6, 1.0 Hz, 1H), 5.13 – 5.06 (m, 1H), 5.06 – 4.99 (m, 1H), 2.81 – 2.71 (m, 2H), 2.42 (dtd, J= 9.2, 6.5, 1.4 Hz, 2H).
13C NMR (126 MHz, Chloroform-d) δ 142.00, 138.22, 128.56, 128.42, 125.94, 115.04, 35.66, 35.54.
The 1H and 13C NMR spectra are in agreement with those reported in the literature.12
12Liu, R.; Lu, Z.; Hu, X.; Li, J.; Yang, X. Org. Lett. 2015, 17, 1489-1492

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