of 248
S
1
Nickel
-
Catalyzed Reductive Alkylation of Heteroaryl Imines
Raymond F. Turro
,
Marco Brandstätter
, Sarah E. Reisman
*
The Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering
Division of Chemistry and Chemical
Engineering, California Institute of Technology
Pasadena, California 911
2
5
*reisman@caltech.edu
Supporting Information
Table of Contents
1.
Experimental Details ..........................................................................................
S
3
2.
Optimization of Reaction Parameters
Procedure
...............................................
S
5
3.
Substrate Preparation
.........................................................................................
S
5
3.1.
Synthesis of Heteroaryl Imines
..............................................................
S
5
3.2.
Synthesis of
N
-
hydroxyphthalimide
(NHP)
Ester Substrates
................
S
16
4.
Nickel
-
Catalyzed
Alkyl
ation of
Heteroaryl Imines
...........................................
S
1
7
4.1.
General procedure
3
: Reaction on 0.3 mmol scale
................................
S
17
4.2.
Challenging Substrates
..........................................................................
S
17
4.3.
Product Distri
b
ution for Reactions with
1a
and Alkyl Halides
........
....
S
18
4.4.
Characterization of Reaction Products:
Scheme 1
................................
S
18
5.
Mechanistic Experiments
.........................................
..........................
...............
S
42
5.1.
Imine
Homocoupling
.........................
...........................................
.
.......
S
42
5.2.
Probing Intermediacy of Organomanganese Intermediate
.............
.
......
S
4
4
5.3.
Stoichiometric Ni
0
Alkylation
(Scheme
3
)
.........................................
..
.
S
4
5
S
2
5.4.
Synthesis of
1a
2
MCl
2
complexes
10
and
11
..................................
.
.
...
S
4
6
5.5.
Preparation of
(1a)
2
Ni
I
complex
and Spectroscopic Analysis
............
S
4
7
5.6.
Alternative Radical Generation Approaces for Alkylation ................ S
50
5.7.
Stir
Rate Study .................................................................................... S
5
2
5.8.
Exogenous Ligands and Electron Mediators ...................................... S
5
2
6.
Electroanalytical Experiments
..........................................
.............................. S
5
2
6.1.
Cyclic Voltammetry
of Heteroaryl Imines
and Metal Complexes
.....
S
5
3
6.2.
Effect of Reaction components on
1
0
................................................
S
5
6
6.3.
Kinetics
of
Reaction of Reduced
1
0
(
1
0
red
)
and Benzyl Chloride
.....
S
5
8
7.
UV/Vis and Spectroelectrochemistry
........................................................
.
.... S
6
3
7.1.
UV/Vis of independently synthesized complexes
......................
.
.......
S
6
3
7.2.
Spectroelectrochemistry on
1
0
...........................................................
S
6
5
8.
Electrocatalytic Imine Alkylation
..................................................................
S
6
7
8.1.
General
Procedure 4:
Electrolysis
on 1.2 mmol
S
cale
.......................
S
6
7
8.2.
Optimization of Electroreductive Alkylation Reaction
......................
S
6
8
8.3.
Characterization of Reaction Products
:
Scheme
2
.............................
S
6
9
9.
Computational Details
...................................................................................
S
7
2
9.1.
DFT Input Files and Coordinates
...................................................... S
7
2
9.2.
Calculated Geometries of
9
and
9
ox
................................................... S
8
5
9.3.
Qualitative MO Diagram
of
9
............................................................ S8
7
10.
X
-
Ray Data
...............................................................................................
..... S
8
7
11.
Elemental Analysis of Commercial Mn
0
....................................................... S
91
12.
References
...................................................................................................... S
9
4
13.
1
H NMR and
13
C NMR
Spectra
..................................................................... S
9
4
S
3
1.
Experimental Details
Materials and
Methods
Unless otherwise stated, reactions were performed under a N
2
atmosphere using freshly dried
solvents.
All reagents were purchased f
rom commercial suppliers (Sigma Aldrich, Combi
-
Blocks, TCI, Enamine, Strem) and used without further purification unless mentioned
otherwise.
Tetrahydrofuran (THF)
and
methylene chloride (CH
2
Cl
2
)
were dried by passing
through activated alumina columns. An
hydro
us
N
-
methylpyrrolidinone (NMP) w
as
purchased
from Aldrich and stored
in a
N
2
-
filled
glovebox
.
NiCl
2
·dme was purchased from Strem and
stored in the glovebox.
Manganese powder (
~
325 mesh, 99.3%) was purchased from Alfa
Aesar. Zinc dust (97.5%) was purchased from Strem.
R
eactions were monitored by thin
-
layer
chromatography using EMD/Merck silica gel 60 F254 pre
-
coated plates (0.25 mm) and were
visualized by UV,
p
-
Anisaldehyde,
Ninh
ydrin
, or KMnO
4
staining. Flash column
chromatography was performed as described by Still et al. using silica gel (230
-
400 mesh,
Silicycle).
1
Purified compounds were dried on a high vacuum line (0.2 torr) to remove trace
solvent.
1
H and
13
C NMR spectra we
re recorded on a Bruker Avance III HD with Prodigy
cryoprobe
(at 400 MHz and 101 MHz, respectively), a Varian 400 MR (at 400 MHz and 101
MHz, respectively), or a Varian Inova 500 (at 500 MHz and 126 MHz, respectively).
1
H and
19
F NMR spectra were also reco
rded on a Varian Inova 300 (at 300 MHz and 282 MHz,
respectively). NMR data is reported relative to internal CHCl
3
(
1
H, δ = 7.26)
and
CDCl
3
(
13
C,
δ = 77.0)
.
CDCl
3
for NMR spectra on amine
-
containing compounds was passed through basic
alumina.
Data for
1
H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity,
coupling constant (Hz), integration). Multiplicity and qualifier abbreviations are as fo
llows: s
= singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. IR spectra were recorded
on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm
1
). HRMS were acquired from the Caltech Mass Spectral
Facility using fast
-
atom bombardment
(FAB), electrospray ionization (ESI
-
TOF),
Field Desorption (FD),
or electron impact (EI).
E
lemental analysis (EA)
with ICP
-
MS
on
a
commercial manganese sample
(mentioned above)
w
as
performed
at
the
Resnick Sustainabili
ty Institute's Water and Environment Lab at the
California Institute of Technology
.
X
-
ray diffraction
was
performed at the Caltech X
-
ray
Crystal Facility.
The computations presented here were conducted on the
Resnick
High
Performance Cluster,
a facility su
pported by
the Resnick Sustainability Institute at the
California Institute of Technology.
Electroanalytical and spectroelectrochemical experiments
S
4
were conducted in the Beckman Resource Laser Resource Center at the Cal
ifornia
Institute of
Technology.
S
5
2.
Op
timization of Reaction Parameters
(
Table 1
)
General Procedure:
To a 1
-
dram vial equipped with a stir bar
(1.2 cm)
was
added
2
-
imino
pyridine
1a
(0.
3
mmol), benzyl bromide (0.
36
mmol,
1.2
equiv)
,
and
reductant
(
Mn
0
,
0.
3
mmol,
1.0 equiv
; Zn
0
, 0.6 mmol, 2.0 equiv; TDAE, 0.45 mmol, 1.5 equiv
) on the benchtop
(or
in
the
glovebox in the case of TDAE
following the solvent addition
)
. The vial was brought into a
nitrogen
-
filled glovebox and a stock solution of
metal catalyst
in NMP (0.
75
ml, 0.0
2
M,
0.
05
equiv [
M
]) and
additive (
TMSCl
,
0.
6
mmol, 2.0 equiv
; AcOH, 0.3 mmol, 1 equiv; HFIP, 1.5
mmol, 5 equiv
)
was added
. The vial w
as
sealed with a Teflon cap, removed from the glovebox,
and stirred
at ambient temperature
for 14 hours at
60
0 rpm. The resulting suspension was
diluted with CH
2
Cl
2
(0.5 ml) and extracted 3x with 1
N HCl (0.5 ml). To the combined aqueous
phases was added K
2
C
O
3
(s) until gas evolution ceased. The resulting aqueous solution was
extracted 3x with EtOAc and the combined
EtOAc layers
were concentrated
under reduced
pressure then further concentrated at
3
0 °C until most of the NMP was removed
and analyzed
by
1
H NMR
with 1,1,2,2
-
tetrachloroet
ha
ne as an
internal
standard
to obtain
a quantitative NMR
yield.
For electrochemical reaction procedure (Table 1, entry 16
-
17) see General Procedure 4.
3.
Substrate Preparation
3.1.
Synthesis of Heteroaryl Imines
a. General Procedure 1: Heteroaryl Imine
Synthesis using Volatile Amines
A 1
-
dram vial equipped with a stir bar was charged with MeOH (0.7 M), heteroaryl
aldehyde
(1.0 equiv), and primary amine RNH
2
(1.
1
-
1.5
equiv). The resulting solution was stirred at
room temperature for 2 hours, followed by concentration in vacuo. The resul
ting 2
-
imino
-
heteroar
ene
was obtained in pure form and used without further purification.
b. General Procedure 2: Heteroaryl Imine Synthesis using
N
on
-
volatile
A
mines
A 1
-
dram vial equipped with a stir bar was charged with CH
2
Cl
2
(0.7 M), heteroaryl aldeh
yde
(1.05 equiv), MgSO
4
(1.5 equiv) and primary amine RNH
2
(1.0 equiv). The resulting solution
was stirred at room temperature for 18 hours. The resulting suspension was filtered and
N
O
N
N
R
RNH
2
(1.2 equiv)
MeOH, rt
Het
Het
S
6
concentrated in vacuo. The resulting 2
-
imino
-
heteroaryl was obtained in
pure form and used
without further purification.
(
E
)
-
N
-
isopropyl
-
1
-
(pyridin
-
2
-
yl)methanimine (
1a
)
Prepared from 2
-
pyridine carboxaldehyde (
2.30 g
,
21.5
mmol)
and
isopropylamine (1.59 g, 26.8 mmol)
following General Procedure 1. After
concentration in vacuo,
1a
(
2.68
g,
18.1
mmol,
84
%) was obtained as a
yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ 8.63 (d,
J
= 3.1 Hz, 1H), 8.39 (s, 1H), 7.98 (d,
J
= 7.9 Hz,
1H), 7.73 (td,
J
= 7.9, 2.2 Hz, 1H), 7.29 (ddd
,
J
= 7.5, 4.8, 1.2 Hz, 1H), 3.69
3.60 (m, 1H),
1.29 (d,
J
= 6.3 Hz, 6H).
13
C NMR (126 MHz, CDCl
3
):
δ 159.5, 155.0, 149.6, 136.7, 124.8, 121.6, 61.7, 24.2.
FTIR (NaCl, thin film, cm
-
1
):
3056, 2968, 2929, 2865, 1647, 1588, 1568, 1466, 1437, 1362,
1316, 11
39, 993, 973, 945, 775, 744, 615.
HRMS (FAB, m/z):
calc’d for C
9
H
11
N
2
[M+H]
+
H
2
: 147.0922; found 147.0922.
(
E
)
-
N
-
butyl
-
1
-
(pyridin
-
2
-
yl)methanimine (
1b
)
Prepared fro
m
2
-
pyridine carboxaldehyde (
1.07
g,
10.0
mmol)
and
n
-
butylamine (878 mg, 12.0
mmol)
following General Procedure 1. After
concentration in vacuo,
1b
(
1.30
g,
8.00
mmol,
80
%) was obtained as
a yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ
8.64 (d,
J
= 4.8 Hz, 1H), 8.37 (s, 1H), 7.97 (d,
J
= 7.9 Hz,
1H), 7.73 (td,
J
= 7.7, 1.7 Hz, 1H), 7.30 (dd,
J
= 7.5, 4.8 Hz, 1H), 3.68 (t,
J
= 6.8 Hz, 2H), 1.71
(p,
J
= 7.1 Hz, 2H), 1.40 (h,
J
= 7.4 Hz, 2H), 0.95 (t,
J
= 7.4 Hz, 3H).
13
C NMR (126 MHz, CDCl
3
):
δ
161.9, 154.8, 149.6, 136.8, 124.8, 121.4, 61.5, 33.0, 20.6,
14.1.
FTIR (NaCl, thin film, cm
-
1
):
3053, 3009, 2958, 293
8
, 2872, 1649, 1587, 1567, 1468, 1436,
1377, 1332, 1292, 1227, 1145, 1117, 1066, 1044, 992, 978, 939, 898, 864, 775, 743, 654, 617.
HRMS (
FAB
, m/z):
calc’d for C
10
H
15
N
2
[M+H]
+
: 16
3
.
1235
; found 16
3
.
1256
.
(
E
)
-
N
-
tert
-
butyl
-
1
-
(pyridin
-
2
-
yl)methanimine (
1c
)
N
N
Me
N
N
Me
Me
S
7
Prepared from 2
-
pyridine carboxaldehyde (
225
mg,
2.10
mmol)
and
tert
-
butlyamine (185 mg, 2.52 mmol)
following General Procedure 1. After
concentration in vacuo,
1c
(
3
26
mg,
2.0
mmol,
95
%) was obtained as a
yellow oil.
1
H NMR (500 MHz, CDCl
3
):
δ
8.66
8.58 (m, 1H), 8.35 (s, 1H), 8.01 (dt,
J
= 7.9, 1.1 Hz,
1H), 7.76
7.67 (m, 1H), 7.28 (ddd,
J
= 7.5, 4.9, 1.3 Hz, 1H), 1.31 (s, 9H).
13
C NMR (126 MHz, CDCl
3
):
δ
156.6, 155.7, 149.5, 136.7, 124.6, 121.2,
58.0, 29.8.
FTIR (NaCl, thin film, cm
-
1
):
3056, 2969, 2931, 1646, 1588, 1568,
1467, 1436, 1228, 1209,
1044, 994, 972, 908, 860, 775, 744, 616.
HRMS (ESI
-
TOF, m/z):
calc’d for C
10
H
15
N
2
[M+H]
+
: 1
63
.
1235
; found 16
3.1210
.
(
E
)
-
N
-
cyclopropyl
-
1
-
(pyridin
-
2
-
yl)
methanimine (
1d
)
Prepared from 2
-
pyridine carboxaldehyde (
225
mg,
2.10
mmol)
and
cyclopropylamine (144 mg, 2.52 mmol
following General Procedure 1. After
concentration in vacuo,
1d
(
200
mg,
1.37
mmol,
65
%) was obtained as a
yellow oil.
1
H NMR (500 MHz, C
DCl
3
):
δ
7.88 (d,
J
= 9.0 Hz, 1H), 7.71 (td,
J
= 7.7, 1.7 Hz, 1H), 7.31
7.24 (m, 1H), 3.13 (hept,
J
= 6.8, 3.4 Hz, 1H), 1.09
1.04 (m, 2H), 1.03
0.97 (m, 2H).
13
C NMR (126 MHz, CDCl
3
):
δ
159.3, 154.8, 149.6, 136.6, 124.4, 121.3, 42.2, 9.5.
FTIR
(NaCl, thin film, cm
-
1
):
3420, 3055, 3010, 2962, 2878, 1635, 1583, 1568, 1470, 1436,
1381, 1320, 1174, 1146, 1090, 1042, 956, 887, 812, 773, 743, 612.
HRMS (
FAB
, m/z):
calc’d for C
9
H
11
N
2
[M+H]
+
: 147.0922; found 147.0922.
(
E
)
-
N
-
cyclobutyl
-
1
-
(pyridin
-
2
-
yl)m
ethanimine (
1e
)
Prepared from 2
-
pyridine carboxaldehyde (
225
mg,
2.10
mmol)
and
cyclobutylamine (179 mg, 2.52 mmol)
following General Procedure 1. After
concentration in vacuo,
1e
(
243
mg,
1.51
mmol,
72
%) was obtained as a
yellow oil.
1
H NMR (500
MHz, CDCl
3
):
δ
8.6 (d,
J
= 4.8 Hz, 1H), 8.3 (d,
J
= 1.7 Hz, 1H), 8.0 (d,
J
= 7.9
Hz, 1H), 7.7 (td,
J
= 7.7, 1.7 Hz, 1H), 7.3 (dd,
J
= 6.4, 4.8 Hz, 1H), 4.3
4.2 (m, 1H), 2.4
2.3
(m, 2H), 2.3
2.1 (m, 2H), 1.9
1.8 (m, 2H).
13
C NMR (126 MHz, CDCl
3
):
δ
159.4, 154.9, 149.6, 136.7, 124.8, 121.4, 62.9, 30.5, 15.8.
N
N
Me
Me
Me
N
N
N
N
S
8
FTIR (NaCl, thin film, cm
-
1
):
3055, 2980, 2939, 2868, 1642, 1589, 1567, 1469, 1436, 1374,
1319, 1228, 1140, 1080, 1042, 992, 972, 861, 773, 743.
HRMS (
FAB
, m/z):
calc’d for C
10
H
13
N
2
[M+H]
+
: 16
1
.
1079
; found 16
1
.
1086
.
(
R
,
E
)
-
N
-
(1
-
phenylethyl)
-
1
-
(pyridin
-
2
-
yl)methanimine (
1
f
)
Prepared from 2
-
pyridine carboxaldehyde (
176
mg,
1.65
mmol)
and (
R
)
-
(+)
-
1
-
phenethylamine (190 mg, 1.57 mmol)
following General Procedure
2
.
After concentration in vacuo,
1f
(
82.4
mg,
0.39
mmol,
25
%) was obtained
as
tan solid
.
1
H NMR (500 MHz, CDCl
3
):
δ
8.64 (ddd,
J
= 4.9, 1.7, 0.9 Hz, 1H), 8.47 (s, 1H), 8.10 (dt,
J
= 7.9, 1.1 Hz, 1H), 7.78
7.67 (m, 1H), 7.46
7.41 (m, 2H), 7.38
7.32 (m, 2H), 7.30 (ddd,
J
= 7.5, 4.8, 1.2 Hz, 1H), 7.28
7.22 (m, 1H), 4.65 (q,
J
= 6.4 Hz, 1H), 1.61 (d,
J
= 6.7 Hz, 3H).
13
C NMR (126 MHz, CDCl
3
):
δ
160.6, 155.0, 149.5, 144.8, 136.7
, 128.7, 127.2, 126.9, 124.9,
121.7, 69.8, 24.8.
FTIR (NaCl, thin film, cm
-
1
):
3059, 3027, 2972, 2927,
2861, 1646, 1586, 1568, 1491, 1466,
1456, 1436, 1373, 1338, 1304, 1080, 993, 973, 908, 763, 700.
HRMS (
FAB
, m/z):
calc’d for C
14
H
15
N
2
[M+H]
+
:
211
.
1235
; f
ound
211
.
1217
.
(
E
)
-
N
-
isopropyl
-
1
-
(pyridin
-
2
-
yl)ethan
-
1
-
imine
(
1
g
)
Prepared from 2
-
acetylpyridine
(
162
mg,
1.34
mmol)
and isopropylamine
(95.2 mg, 1.61 mmol
following
General Procedure 1
modified
with the
addition of 3
Å
molecular sieves (350mg, 2.2 mass equiv)
to allow the
reaction to run for 48 hours
. After concentration in vacuo,
1g
(
126
mg,
0.78
mmol,
58
%) was obtained as a yellow oil.
1
H NMR (
400
MHz,
CD
2
Cl
2
):
δ
8.46 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 7.98 (dt, J =
8.0, 1.1 Hz,
1H), 7.60 (ddd, J = 8.0, 7.4, 1.8 Hz, 1H), 7.18 (ddd, J = 7.4, 4.8, 1.3 Hz, 1H), 3.83 (hept, J =
6.3 Hz, 1H), 2.25 (s, 3H), 1.11 (d, J = 6.2 Hz, 6H).
13
C NMR (101 MHz, CD
2
Cl
2
):
δ
163.19, 158.28, 148.07, 135.98, 123.76, 120.63, 51.46,
23.20, 12
.98.
FTIR (NaCl, thin film, cm
-
1
):
3050
, 2967, 2929, 2869, 1638, 1585, 1565, 1464, 1433, 1368,
1297, 1134, 1098, 1043, 991, 783, 743.
HRMS (
FAB
, m/z):
calc’d for C
10
H
15
N
2
[M+H]
+
:
163.1235; found: 163.1231.
N
N
Me
Ph
N
Me
N
Me
Me